Influence of CYP19A1 gene expression levels in women with breast cancer: a systematic review of the literature

Maria da Conceição Barros-Oliveira Danylo Rafhael Costa-Silva Alesse Ribeiro dos Santos Renato Oliveira Pereira José Maria Soares-Júnior Benedito Borges da Silva About the authors

Abstract

Breast cancer is the most frequently diagnosed malignant neoplasm in women and is considered a multifactorial disease of unknown etiology. One of the major risk factors is genetic alteration. Changes in CYP19A1 gene expression levels have been associated with increased risk and increased aggressiveness of breast cancer. Increased CYP19A1 gene expression and/or aromatase activity are among the major regulatory events for intratumoral production of estrogens in breast malignant tissues. This systematic review aimed to investigate the influence of CYP19A1 gene expression levels in women with breast cancer. The research was carried out using the PubMed, Scopus, and Web of Science databases. Searches were conducted between February 2 and May 15, 2019. Inclusion criteria were studies published between 2009 and 2019, English language publications, and human studies addressing the gene expression of CYP19A1 in breast cancer.

A total of 6.068 studies were identified through PubMed (n=773), Scopus (n=2,927), and the Web of Science (n=2,368). After selecting and applying the inclusion and exclusion criteria, six articles were included in this systematic review.

This systematic review provides evidence that increased or decreased levels of CYP19A1 gene expression may be related to pathological clinical factors of disease, MFS, OS, DFS, WATi, markers of metabolic function, concentrations of E1, FSH, and in the use of multiple exons 1 of the CYP19A1 gene in breast cancer.

Breast Cancer; Aromatase; CYP19A1; Estrogens; Gene Expression


INTRODUCTION

Cancer is a serious global health problem, and its incidence and mortality are growing rapidly globally (11. Limonta P, Moretti RM, Marzagalli M, Fontana F, Raimondi M, Montagnani Marelli M. Role of Endoplasmic Reticulum Stress in the Anticancer Activity of Natural Compounds. Int J Mol Sci. 2019;20(4):961. https://doi.org/10.3390/ijms20040961
https://doi.org/10.3390/ijms20040961...
). Among women, breast cancer is the most frequently diagnosed malignant neoplasm in the vast majority of countries and is also the leading cause of cancer death (22. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. https://doi.org/10.3322/caac.21492.
https://doi.org/10.3322/caac.21492...
). In 2018, an estimated 2.1 million new cases of breast cancer were diagnosed worldwide (33. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piãeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-53. https://doi.org/10.1002/ijc.31937.
https://doi.org/10.1002/ijc.31937...
). Geographic differences influence the incidence and mortality of breast cancer worldwide; the highest incidence rates occur in more developed regions (44. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86. https://doi.org/10.1002/ijc.29210.
https://doi.org/10.1002/ijc.29210...
).

Breast cancer is a multifactorial disease of unknown etiology. One of the main risk factors is genetic alteration (55. Costa-Silva DR, da Conceição Barros-Oliveira M, Borges RS, Campos-Verdes LM, da Silva-Sampaio JP, Escorcio-Dourado CS, et al. Insulin-like growth factor 1 gene polymorphism in women with breast cancer. Med Oncol. 2017;34(4):59. https://doi.org/10.1007/s12032-017-0915-4
https://doi.org/10.1007/s12032-017-0915-...
,66. Campos-Verdes LM, da Silva-Sampaio JP, Costa-Silva DR, de Oliveira VA, Junior AMC, Silva VC, et al. Genetic polymorphism of calcium-sensing receptor in women with breast cancer. Med Oncol. 2018;35(3):23. https://doi.org/10.1007/s12032-018-1089-4
https://doi.org/10.1007/s12032-018-1089-...
). Genetic mutations of breast cancer, BRCA 1 and 2, are related to the increased risk of developing hereditary breast and ovarian cancer over time (77. Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269-75. https://doi.org/10.1002/cncr.29041.
https://doi.org/10.1002/cncr.29041...
). However, the involvement of genes in breast cancer has not yet been fully elucidated (55. Costa-Silva DR, da Conceição Barros-Oliveira M, Borges RS, Campos-Verdes LM, da Silva-Sampaio JP, Escorcio-Dourado CS, et al. Insulin-like growth factor 1 gene polymorphism in women with breast cancer. Med Oncol. 2017;34(4):59. https://doi.org/10.1007/s12032-017-0915-4
https://doi.org/10.1007/s12032-017-0915-...
,66. Campos-Verdes LM, da Silva-Sampaio JP, Costa-Silva DR, de Oliveira VA, Junior AMC, Silva VC, et al. Genetic polymorphism of calcium-sensing receptor in women with breast cancer. Med Oncol. 2018;35(3):23. https://doi.org/10.1007/s12032-018-1089-4
https://doi.org/10.1007/s12032-018-1089-...
,88. Campos-Verdes LM, Costa-Silva DR, da Silva-Sampaio JP, Barros-Oliveira MDC, Escórcio-Dourado CS, Martins LM, et al. Review of Polymorphism of the Calcium-Sensing Receptor Gene and Breast Cancer Risk. Cancer Invest. 2018;36(2):1-7. https://doi.org/10.1080/07357907.2018.1430817.
https://doi.org/10.1080/07357907.2018.14...
). Some authors have described a significant association between the levels of gene expression of CYP19A1 and breast cancer, however there is a need for further elucidation of the association between these levels and increased risk of breast cancer, survival, and disease progression (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...

10. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
-1111. Friesenhengst A, Pribitzer-Winner T, Miedl H, Pröstling K, Schreiber M. Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer. Horm Cancer. 2018;9(2):128-38. https://doi.org/10.1007/s12672-017-0317-2.
https://doi.org/10.1007/s12672-017-0317-...
).

The CYP19A1 gene encodes the aromatase enzyme belonging to the cytochrome p450 superfamily. The enzyme is located in the endoplasmic reticulum of estrogen producing cells and is considered the key enzyme that catalyzes the final step in estrogen biosynthesis and promoting the aromatization of androgens in estrogens (1212. Hong Y, Li H, Yuan YC, Chen S. Molecular characterization of aromatase. Ann N Y Acad Sci. 2009;1155:112-20. https://doi.org/10.1111/j.1749-6632.2009.03703.x.
https://doi.org/10.1111/j.1749-6632.2009...

13. Chan HJ, Petrossian K, Chen S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J Steroid Biochem Mol Biol. 2016;161:73-83. https://doi.org/10.1016/j.jsbmb.2015.07.018.
https://doi.org/10.1016/j.jsbmb.2015.07....
-1414. Blackburn HL, Ellsworth DL, Shriver CD, Ellsworth RE. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy. Cancer Causes Control. 2015;26(3):319-32. https://doi.org/10.1007/s10552-014-0519-7.
https://doi.org/10.1007/s10552-014-0519-...
). Its activity is tightly controlled and it is present in a wide variety of human tissues including ovary, testis, placenta, bone, skin, brain, and adipose tissue (1515. Manna PR, Molehin D, Ahmed AU. Dysregulation of Aromatase in Breast, Endometrial, and Ovarian Cancers: An Overview of Therapeutic Strategies. Prog Mol Biol Transl Sci. 2016;144:487-537. https://doi.org/10.1016/bs.pmbts.2016.10.002.
https://doi.org/10.1016/bs.pmbts.2016.10...
,1616. Czajka-Oraniec I, Simpson ER. Aromatase research and its clinical significance. Endokrynol Pol. 2010;61(1):126-34.). In premenopausal women, estrogens are synthesized by ovarian granulosa and corpus luteum cells, while in postmenopausal women, they are synthesized in many extra ovarian tissues, such as adipose tissue and bones (1515. Manna PR, Molehin D, Ahmed AU. Dysregulation of Aromatase in Breast, Endometrial, and Ovarian Cancers: An Overview of Therapeutic Strategies. Prog Mol Biol Transl Sci. 2016;144:487-537. https://doi.org/10.1016/bs.pmbts.2016.10.002.
https://doi.org/10.1016/bs.pmbts.2016.10...
). In addition, aromatase is present in both normal and cancer cells of the mesenchymal stroma and human mammary epithelium. However, higher levels of enzymatic activity and its gene expression are observed in cancer cells (1313. Chan HJ, Petrossian K, Chen S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J Steroid Biochem Mol Biol. 2016;161:73-83. https://doi.org/10.1016/j.jsbmb.2015.07.018.
https://doi.org/10.1016/j.jsbmb.2015.07....
).

The CYP19A1 gene is located on chromosome 15, q21.1 band of the human genome, whose total length is 123 kb, of which 30 kb corresponds to the coding region and 93 kb comprises an untranslated region (1717. To SQ, Knower KC, Cheung V, Simpson ER, Clyne CD. Transcriptional control of local estrogen formation by aromatase in the breast. J Steroid Biochem Mol Biol. 2015;145:179-86. https://doi.org/10.1016/j.jsbmb.2014.05.004.
https://doi.org/10.1016/j.jsbmb.2014.05....
). The CYP19A1 gene consists of 10 untranslated exons ''Is'' (I.1, I.2, 2a, I.3, I.4, I.5, I.6, I.7, If, and PII) and nine translated exons (II-X). The various Is exons are expressed in a manner specific to each tissue and each have their corresponding promoter localized upstream, which is regulated by different mechanisms, so the specific activity of the tissue aromatase is regulated by the alternative use of these exons (1818. Zhao H, Zhou L, Shangguan AJ, Bulun SE. Aromatase expression and regulation in breast and endometrial cancer. J Mol Endocrinol. 2016;57(1):R19-33. https://doi.org/10.1530/JME-15-0310.
https://doi.org/10.1530/JME-15-0310...
,1919. Holloway KR, Barbieri A, Malyarchuk S, Saxena M, Nedeljkovic-Kurepa A, Cameron Mehl M, et al. SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression. Mol Endocrinol. 2013;27(3):480-90. https://doi.org/10.1210/me.2012-1347.
https://doi.org/10.1210/me.2012-1347...
). In normal human breast tissue, most transcripts of the CYP19A1 gene are derived from the I.4 distal promoter (2020. Kim HG, Jin SW, Kim YA, Khanal T, Lee GH, Kim SJ, et al. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells. Food Chem Toxicol. 2017;106(Pt A):232-241. https://doi.org/10.1016/j.fct.2017.05.058.
https://doi.org/10.1016/j.fct.2017.05.05...
,2121. Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SE. Regulation of breast cancer-associated aromatase promoters. Cancer Lett. 2009;273(1):15-27. https://doi.org/10.1016/j.canlet.2008.05.038.
https://doi.org/10.1016/j.canlet.2008.05...
). However, in the presence of cancerous breast tissue, the transfer of the I.4 promoter to the I.3 promoter or PII occurs frequently (2121. Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SE. Regulation of breast cancer-associated aromatase promoters. Cancer Lett. 2009;273(1):15-27. https://doi.org/10.1016/j.canlet.2008.05.038.
https://doi.org/10.1016/j.canlet.2008.05...
,2222. Chand AL, Herridge KA, Howard TL, Simpson ER, Clyne CD. Tissue-specific regulation of aromatase promoter II by the orphan nuclear receptor LRH-1 in breast adipose stromal fibroblasts. Steroids. 2011;76(8):741-4. https://doi.org/10.1016/j.steroids.2011.02.024.
https://doi.org/10.1016/j.steroids.2011....
). This results in a 3- to 4-times increase in transcripts of the CYP19A1 gene in patients with tumors than in patients without tumors (1717. To SQ, Knower KC, Cheung V, Simpson ER, Clyne CD. Transcriptional control of local estrogen formation by aromatase in the breast. J Steroid Biochem Mol Biol. 2015;145:179-86. https://doi.org/10.1016/j.jsbmb.2014.05.004.
https://doi.org/10.1016/j.jsbmb.2014.05....
,2323. Fukami M, Suzuki J, Nakabayashi K, Tsunashima R, Ogata T, Shozu M, et al. Lack of genomic rearrangements involving the aromatase gene CYP19A1 in breast cancer. Breast Cancer. 2014;21(3):382-5. https://doi.org/10.1007/s12282-013-0471-5.
https://doi.org/10.1007/s12282-013-0471-...
).

Epidemiological and experimental evidence indicates that women with malignant tumors of the breast, endometrium, and ovary express high levels of mRNA of CYP19A1 and estrogen receptor (ER) alpha as well as elevated levels of estrogens (2424. Wang X, Simpson ER, Brown KA. Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer. J Steroid Biochem Mol Biol. 2015;153:35-44. https://doi.org/10.1016/j.jsbmb.2015.07.008.
https://doi.org/10.1016/j.jsbmb.2015.07....
). Increased CYP19A1 gene expression and/or aromatase activity are major regulatory events for the intratumoral production of estrogens in these malignant tissues. Thus, this enzyme is a molecular target for therapeutic approaches, including in postmenopausal women where estrogen derived from several sources is the major risk factor in the development and growth of hormone-induced malignancies (2525. Hong Y, Li H, Ye J, Miki Y, Yuan YC, Sasano H, et al. Epitope characterization of an aromatase monoclonal antibody suitable for the assessment of intratumoral aromatase activity. PLoS One. 2009;4(11):e8050. https://doi.org/10.1371/journal.pone.0008050
https://doi.org/10.1371/journal.pone.000...

26. Dunbier AK, Hong Y, Masri S, Brown KA, Sabnis GJ, Palomares MR. Progress in aromatase research and identification of key future directions. J Steroid Biochem Mol Biol. 2010;118(4-5):311-315. https://doi.org/10.1016/j.jsbmb.2009.09.005.
https://doi.org/10.1016/j.jsbmb.2009.09....
-2727. Sjoquist KM, Martyn J, Edmondson RJ, Friedlander ML. The role of hormonal therapy in gynecological cancers-current status and future directions. Int J Gynecol Cancer. 2011;21(7):1328-33. https://doi.org/10.1097/IGC.0b013e31821d6021.
https://doi.org/10.1097/IGC.0b013e31821d...
).

Altered levels of CYP19A1 gene expression may be related to unfavorable outcomes and increased aggressiveness in breast cancer (2020. Kim HG, Jin SW, Kim YA, Khanal T, Lee GH, Kim SJ, et al. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells. Food Chem Toxicol. 2017;106(Pt A):232-241. https://doi.org/10.1016/j.fct.2017.05.058.
https://doi.org/10.1016/j.fct.2017.05.05...
,2828. Mukhopadhyay KD, Liu Z, Bandyopadhyay A, Kirma NB, Tekmal RR, Wang S, et al. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells. PLoS One. 2015;10(4):e0121136. https://doi.org/10.1371/journal.pone.0121136
https://doi.org/10.1371/journal.pone.012...
,2929. Xu YC, Zhang FC, Li JJ, Dai JQ, Liu Q, Tang L, et al. RRM1, TUBB3, TOP2A, CYP19A1, CYP2D6: Difference between mRNA and protein expression in predicting prognosis of breast cancer patients. Oncol Rep. 2015;34(4):1883-94. https://doi.org/10.3892/or.2015.4183.
https://doi.org/10.3892/or.2015.4183...
). However, there is a scarcity of studies on the subject in women with breast cancer. This motivated us to detail, in a systematic review, the studies available in several major databases that investigates the influence of levels of CYP19A1 gene expression in women with breast cancer.

MATERIALS AND METHODS

Data Sources

The research was carried out using the PubMed, Scopus, and Web of Science databases. Searches were conducted between February 2 and May 15, 2019. The search strategy included the crossing of the following descriptors: “breast cancer’’ OR “breast neoplasm’’ AND “CYP19A1’’ OR “aromatase’’ AND “gene’’; “breast cancer’’ OR “breast neoplasm’’ AND “CYP19A1’’ OR “aromatase’’ AND “expression’’; “breast cancer’’ OR “breast neoplasm’’ AND “CYP19A1’’ OR “aromatase’’ AND “mRNA’’; “breast cancer’’ OR “breast neoplasm’’ AND “CYP19A1’’ OR “aromatase’’ AND “gene’’ AND “expression’’.

Study selection and eligibility criteria

A collection of eligibility criteria was used to select articles from the literature. Inclusion criteria were studies published between 2009 and 2019, English language publications, and human studies addressing the gene expression of CYP19A1 in breast cancer. Exclusion criteria were duplicate articles, articles with only abstracts available, literature reviews, editorials, letters to the editor, conference proceedings, and articles related to breast cancer and CYP19A1 that did not quantitatively analyze levels of gene expression.

The titles and abstracts identified from the research were analyzed by two researchers (M.C.B.O and D.R.C.S). After a primary examination, all the complete studies retrieved were subjected to a more detailed evaluation, and compared and verified to ensure equivalence in the selection and analysis of articles. The selection process of the studies was mapped according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines (3030. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. https://doi.org/10.1136/bmj.b2535
https://doi.org/10.1136/bmj.b2535...
).

RESULTS

A total of 6.068 studies were identified through PubMed (n=773), Scopus (n=2,927), and the Web of Science (n=2,368). After selecting and applying the inclusion and exclusion criteria, six articles were included in this systematic review. The flow chart detailing the process of identification, selection, eligibility, and final inclusion of the studies is presented in Figure 1. The description of the selected studies and the primers used in quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis are shown in Tables 1 and 2, respectively.

Figure 1
Flow chart detailing the process of identification, selection, eligibility, and final inclusion of the studies.
Table 1
Description of the selected studies.
Table 2
Primers CYP19A1 used in the qRT-PCR analysis from previous studies.

Friesenhengst et al. (1111. Friesenhengst A, Pribitzer-Winner T, Miedl H, Pröstling K, Schreiber M. Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer. Horm Cancer. 2018;9(2):128-38. https://doi.org/10.1007/s12672-017-0317-2.
https://doi.org/10.1007/s12672-017-0317-...
) analyzed the expression of CYP19A1 mRNA in breast cancer tumors and showed that expression levels were significantly elevated in postmenopausal breast cancer patients with an initial diagnosis >50 years. These showed a decrease in metastasis-free survival (MFS), overall survival (OS), and disease-free survival (DFS). In addition, those that were ER positive progressed to metastasis and/or recurrent disease <8 years after diagnosis and all ER positive patients with high CYP19A1 mRNA expression developed pulmonary and bone metastases within 10 years after diagnosis.

Brown et al. (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...
) studied the effect of menopausal status on CYP19A1 mRNA expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction in women undergoing mastectomy for treatment or prevention of breast cancer. Significantly higher levels of CYP19A1 mRNA were observed in all women with high BMI. However, the postmenopausal group had the highest expression, as WATi and markers leptin, high sensitivity C-reactive protein (hsCRP), adiponectin, and cholesterol were also associated with increased mRNA CYP19A1 in the postmenopausal group only.

Tüzüner et al. (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
) compared the expression of CYP19A1 mRNA intumoral, peritumoral, and normal mammary tissues among women with and without breast cancer, and reported a significant increase in the expression of CYP19A1 mRNA in peritumoral tissues. In addition, levels were also elevated in patients with axillary invasion, family history of cancer, and parity after 30 years. On the other hand, low levels of CYP19A1 mRNA were evident in patients with early menarche, null parity, and over 50 years of age. There were no significant associations between factors, such as BMI, smoking, and alcohol consumption.

Bollet et al. (3131. Bollet MA, Savignoni A, De Koning L, Tran-Perennou C, Barbaroux C, Degeorges A, et al. Tumor aromatase expression as a prognostic factor for local control in young breast cancer patients after breast-conserving treatment. Breast Cancer Res. 2009;11(4):R54. https://doi.org/10.1186/bcr2343
https://doi.org/10.1186/bcr2343...
) analyzed the relationship between locoregional recurrence, clinical pathological factors, and intratumoral levels of gene expression of 17 proliferative genes, including the CYP19A1 gene, in women with premenopausal breast cancer. No correlation was observed between CYP19A1 gene expression and pathological clinical factors such as histologic subtype, BMI, and others. Nevertheless, decreased levels of expression were significantly associated with an increase in the rate of locoregional recurrence in these women.

Savolainen-Peltonen et al. (3232. Savolainen-Peltonen H, Vihma V, Wang F, Turpeinen U, Hämäläinen E, Haanpää M, et al. Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer. Gynecol Endocrinol. 2018;34(12):1039-43. https://doi.org/10.1080/09513590.2018.1474868.
https://doi.org/10.1080/09513590.2018.14...
) compared estrogen levels of adipose tissue (AT) and the expression of genes related to estrogen metabolism, including the CYP19A1 gene, in women with and without premenopausal breast cancer. Estrone (E1) concentrations of AT correlated positively with CYP19A1 mRNA expression, as did high BMI. Serum follicle stimulating hormone (FSH) and follicular phase correlated negatively with CYP19A1 mRNA expression in women with breast cancer compared to controls.

Honma et al. (3333. Honma N, Takubo K, Sawabe M, Arai T, Akiyama F, Sakamoto G, et al. Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years. Breast Cancer Res. 2009;11(4):R48. https://doi.org/10.1186/bcr2335
https://doi.org/10.1186/bcr2335...
) investigated the preference of using multiple exons 1 of the CYP19A1 gene in elderly and young women with and without breast cancer. Exon 1d of the CYP19A1 gene was used much more often in tissues of elderly women than in the control group, regardless of whether the tissue was cancerous or normal. Carcinomas of elderly women (EldCa) exhibited significantly higher levels of CYP19A1 mRNA than normal tissues of elderly women (EldNorm), there being no significant difference between carcinomas of controls (ContCa) and normal tissues of controls (ContNorm). EldCa showed significantly higher CYP19A1 mRNA levels than ContCa. In addition, increased levels of mRNA were observed in EldCa with mucinous carcinomas.

DISCUSSION

This systematic review was conducted with the prospect of investigating the potential influence of CYP19A1 gene expression levels in women with breast cancer. Most of the studies evaluated have shown controversial results related to the gene expression of CYP19A1 in women with breast cancer.

Postmenopausal women with ER positive breast cancer with high CYP19A1 gene expression had a significant reduction in MFS, OS, and DFS when compared to premenopausal women with ER negative breast cancer (1111. Friesenhengst A, Pribitzer-Winner T, Miedl H, Pröstling K, Schreiber M. Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer. Horm Cancer. 2018;9(2):128-38. https://doi.org/10.1007/s12672-017-0317-2.
https://doi.org/10.1007/s12672-017-0317-...
). These findings appear to be biologically justifiable since the CYP19A1 gene encodes the aromatase enzyme that is part of the biosynthesis of estrogens and exerts its effects of promoting breast cancer mainly through the ER (3434. Patel S. Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review. J Steroid Biochem Mol Biol. 2017;168:19-25. https://doi.org/10.1016/j.jsbmb.2017.01.009.
https://doi.org/10.1016/j.jsbmb.2017.01....

35. Kidokoro K, Ino K, Hirose K, Kajiyama H, Hosono S, Suzuki T, et al. Association between CYP19A1 polymorphisms and sex hormones in postmenopausal Japanese women. J Hum Genet. 2009;54(2):78-85. https://doi.org/10.1038/jhg.2008.11.
https://doi.org/10.1038/jhg.2008.11...
-3636. Germain D. Estrogen carcinogenesis in breast cancer. Endocrinol Metab Clin North Am. 2011;40(3):473-84, vii. https://doi.org/10.1016/j.ecl.2011.05.009
https://doi.org/10.1016/j.ecl.2011.05.00...
). In addition, elevated levels of CYP19A1 mRNA were significantly associated with local recurrence and incidence of metastases, as well as death related to breast cancer (3737. Salhab M, Reed MJ, Al Sarakbi W, Jiang WG, Mokbel K. The role of aromatase and 17-beta-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast câncer. Breast Cancer Res Treat. 2006;99(2):155-62. https://doi.org/10.1007/s10549-006-9198-8.
https://doi.org/10.1007/s10549-006-9198-...
). However, other studies did not reveal prognostic significance of CYP19A1 mRNA and aromatase enzyme activity in women with postmenopausal breast cancer (3838. Miyoshi Y, Ando A, Hasegawa S, Ishitobi M, Taguchi T, Tamaki Y, et al. High expression of steroid sulfatase mRNA predicts poor prognosis in patients with estrogen receptor-positive breast cancer. Clin Cancer Res. 2003;9(6):2288-93.

39. Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, et al. Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast. Breast Cancer Res. 2003;5(6):R250-6. https://doi.org/10.1186/bcr657.
https://doi.org/10.1186/bcr657...
-4040. Licznerska BE, Wegman PP, Nordenskjöld B, Wingren S. In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients. Breast Cancer Res Treat. 2008;112(1):15-23. https://doi.org/10.1007/s10549-007-9819-x.
https://doi.org/10.1007/s10549-007-9819-...
) or ER positive (4141. Girault I, Lerebours F, Tozlu S, Spyratos F, Tubiana-Hulin M, Lidereau R, et al. Real-time reverse transcription PCR assay of CYP19 expression: application to a well-defined series of post-menopausal breast carcinomas. J Steroid Biochem Mol Biol. 2002;82(4-5):323-32. https://doi.org/10.1016/S0960-0760(02)00190-5.
https://doi.org/10.1016/S0960-0760(02)00...
).

Brown et al. (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...
) and Tüzüner et al. (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
) showed conflicting results concerning the levels of CYP19A1 mRNA expression related to BMI in postmenopausal patients. Although the more than half (55%) of the patients in the Tüzüner et al. (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
) study displayed high BMI, no association was observed with CYP19A1 mRNA expression. The small number of cases of breast cancer and postmenopausal women may have been one of the limitations of the study that led to this outcome. Brown et al. (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...
) showed that a BMI ≥25 kg/m2 was associated with higher levels of CYP19A1 mRNA in postmenopausal women, which may be justified by weight gain during the menopausal transition that has been attributed to hormonal changes, decreased physical activity, and increased energy consumption, which would influence the levels of gene expression (4242. Sutton-Tyrrell K, Zhao X, Santoro N, Lasley B, Sowers M, Johnston J, et al. Reproductive hormones and obesity: 9 years of observation from the Study of Women's Health Across the Nation. Am J Epidemiol. 2010;171(11):1203-13. https://doi.org/10.1093/aje/kwq049.
https://doi.org/10.1093/aje/kwq049...
,4343. Gibson CJ, Thurston RC, El Khoudary SR, Sutton-Tyrrell K, Matthews KA. Body mass index following natural menopause and hysterectomy with and without bilateral oophorectomy. Int J Obes (Lond). 2013;37(6):809-13.).

The high expression of the CYP19A1 gene was related to the increase in WATi and some markers of metabolic function in patients with postmenopausal breast cancer (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...
). Iyengar et al. (4444. Iyengar NM, Morris PG, Zhou XK, Gucalp A, Giri D, Harbus MD, et al. Menopause is a determinant of breast adipose inflammation. Cancer Prev Res (Phila). 2015;8(5):349-58. https://doi.org/10.1158/1940-6207.
https://doi.org/10.1158/1940-6207...
) also described an increased association between CYP19A1 and WATi gene expression levels in postmenopausal women. These data suggest that WATi may contribute to increased local production of estrogen after menopause (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...
). The association of CYP19A1 gene expression levels with metabolic function markers in postmenopausal women has yet to be determined, as it is not known whether these effects occur due to differences in postmenopausal breast cell composition, number of cells adipose stromal, or greater sensitivity to these factors (99. Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606.
https://doi.org/10.1210/jc.2016-3606...
).

There was a significant increase in the levels of CYP19A1 gene expression in the peritumoral tissues of women with breast cancer (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
), supporting findings in the literature that estrogens may diffuse particularly through AT of the breast and then enter the breast duct to stimulate the proliferation of epithelial cells (4545. Simpson ER, Brown KA. Obesity and breast cancer: role of inflammation and aromatase. J Mol Endocrinol. 2013;51(3):T51-9. https://doi.org/10.1530/JME-13-0217.
https://doi.org/10.1530/JME-13-0217...
). Thus, the activity of the aromatase enzyme is almost exclusively for immature adipocytes and fibroblasts related to mammary adipose tissue (4646. Sasano H, Miki Y, Nagasaki S, Suzuki T. In situ estrogen production and its regulation in human breast carcinoma: from endocrinology to intracrinology. Pathol Int. 2009;59(11):777-89. https://doi.org/10.1111/j.1440-1827.2009.02444.x.
https://doi.org/10.1111/j.1440-1827.2009...
). The high expression of the CYP19A1 gene in patients with axillary invasion may be suggested as an additional parameter for the use of adjuvant chemotherapy (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
). The positive regulation of the CYP19A1 gene in the peritumoral tissues of women with a family history of cancer (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
) may be justified by the accumulation of different genotypes for different mutations of the CYP19A1 gene that could affect the levels of gene expression, altering the activity of the aromatase enzyme, and consequently affecting levels of endogenous estrogen (4747. Surekha D, Sailaja K, Rao DN, Padma T, Raghunadharao D, Vishnupriya S. Association of CYP19 polymorphisms with breast cancer risk: A case-control study. J Nat Sci Biol Med. 2014;5(2):250-4. https://doi.org/10.4103/0976-9668.136150.
https://doi.org/10.4103/0976-9668.136150...
,1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
). Patients with high risk factors, such as early onset of menstruation, null parity, and age >50 years, displayed low levels of CYP19A1 gene expression in tumor and peritumoral tissue (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
), unlike the findings of Clemons and Goss (4848. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276-85. https://doi.org/10.1056/NEJM200101253440407.
https://doi.org/10.1056/NEJM200101253440...
). However, late age in pregnancy and association with elevated CYP19A1 gene expression in peritumoral tissue (1010. Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7.
https://doi.org/10.1007/s10528-016-9756-...
) agree with previous studies (4848. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276-85. https://doi.org/10.1056/NEJM200101253440407.
https://doi.org/10.1056/NEJM200101253440...

49. Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Res. 2005;7(3):131-42. https://doi.org/10.1186/bcr1029.
https://doi.org/10.1186/bcr1029...
-5050. Britt K, Ashworth A, Smalley M. Pregnancy and the risk of breast cancer. Endocr Relat Cancer. 2007;14(4):907-33. https://doi.org/10.1677/ERC-07-0137.
https://doi.org/10.1677/ERC-07-0137...
).

On the other hand, the low intratumoral expression of the CYP19A1 gene significantly influenced the increase in locoregional recurrence rate in patients with premenopausal breast cancer (3131. Bollet MA, Savignoni A, De Koning L, Tran-Perennou C, Barbaroux C, Degeorges A, et al. Tumor aromatase expression as a prognostic factor for local control in young breast cancer patients after breast-conserving treatment. Breast Cancer Res. 2009;11(4):R54. https://doi.org/10.1186/bcr2343
https://doi.org/10.1186/bcr2343...
), in agreement with studies in the literature showing decreased levels of CYP19A1 gene expression in premenopausal women (3939. Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, et al. Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast. Breast Cancer Res. 2003;5(6):R250-6. https://doi.org/10.1186/bcr657.
https://doi.org/10.1186/bcr657...
,5151. Yoshimura N, Harada N, Bukholm I, Kåresen R, Børresen-Dale AL, Kristensen VN. Intratumoural mRNA expression of genes from the oestradiol metabolic pathway and clinical and histopathological parameters of breast cancer. Breast Cancer Res. 2004;6(2):R46-55. https://doi.org/10.1186/bcr746.
https://doi.org/10.1186/bcr746...
). Bollet et al. (3131. Bollet MA, Savignoni A, De Koning L, Tran-Perennou C, Barbaroux C, Degeorges A, et al. Tumor aromatase expression as a prognostic factor for local control in young breast cancer patients after breast-conserving treatment. Breast Cancer Res. 2009;11(4):R54. https://doi.org/10.1186/bcr2343
https://doi.org/10.1186/bcr2343...
) suggested that as estrogen represses the CYP19A1 promoter, CYP19A1 mRNA levels could be inversely correlated with high levels of circulating estrogen present in premenopausal patients. Thus, high estrogen levels would reflect low expression of CYP19A1 gene and would be associated with a high recurrence rate in these patients.

E1 concentrations of AT of premenopausal women with breast cancer correlated positively with CYP19A1 mRNA expressions, supporting that active local synthesis of E1 is an important precursor to estradiol in AT in premenopausal women (3232. Savolainen-Peltonen H, Vihma V, Wang F, Turpeinen U, Hämäläinen E, Haanpää M, et al. Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer. Gynecol Endocrinol. 2018;34(12):1039-43. https://doi.org/10.1080/09513590.2018.1474868.
https://doi.org/10.1080/09513590.2018.14...
). The negative expression of the CYP19A1 gene on FSH in these women (3232. Savolainen-Peltonen H, Vihma V, Wang F, Turpeinen U, Hämäläinen E, Haanpää M, et al. Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer. Gynecol Endocrinol. 2018;34(12):1039-43. https://doi.org/10.1080/09513590.2018.1474868.
https://doi.org/10.1080/09513590.2018.14...
) may be explained by the fact that FSH regulates CYP19A1 gene transcription in ovarian granulosa cells and that mRNA expression of this gene is decreased during the luteinization process (5252. Stocco C. Aromatase expression in the ovary: hormonal and molecular regulation. Steroids. 2008;73(5):473-87. https://doi.org/10.1016/j.steroids.2008.01.017.
https://doi.org/10.1016/j.steroids.2008....
,5353. Parakh TN, Hernandez JA, Grammer JC, Weck J, Hunzicker-Dunn M, Zeleznik AJ, et al. Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin. Proc Natl Acad Sci U S A. 2006;103(33):12435-40. https://doi.org/10.1073/pnas.0603006103.
https://doi.org/10.1073/pnas.0603006103...
). Regarding the negative expression of the CYP19A1 gene in the follicular phase of women with breast cancer, the authors suggested the existence of a deregulation of the estrogen synthesis in the TA of the breast with tumor (3232. Savolainen-Peltonen H, Vihma V, Wang F, Turpeinen U, Hämäläinen E, Haanpää M, et al. Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer. Gynecol Endocrinol. 2018;34(12):1039-43. https://doi.org/10.1080/09513590.2018.1474868.
https://doi.org/10.1080/09513590.2018.14...
).

Exon 1d of the CYP19A1 gene was used in a significantly higher proportion in mammary tissues of elderly women than in tissues in the control group, regardless of whether the tissue is cancerous or normal (3333. Honma N, Takubo K, Sawabe M, Arai T, Akiyama F, Sakamoto G, et al. Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years. Breast Cancer Res. 2009;11(4):R48. https://doi.org/10.1186/bcr2335
https://doi.org/10.1186/bcr2335...
). Although these authors suggest that the use of exon 1d of the CYP19A1 gene appears to be a characteristic of the elderly tissue, the specific pattern of use of multiple exons 1 in the elderly mammary tissue has not been described in other studies. Among EldCa, mucinous carcinomas exhibited significantly higher levels of CYP19A1 mRNA than in other carcinomas (3333. Honma N, Takubo K, Sawabe M, Arai T, Akiyama F, Sakamoto G, et al. Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years. Breast Cancer Res. 2009;11(4):R48. https://doi.org/10.1186/bcr2335
https://doi.org/10.1186/bcr2335...
). Mucinous carcinoma is a rare histological type that usually occurs in the elderly (5454. Takuwa H, Tsuji W, Yotsumoto F. Palliative surgery for giant mucinous carcinoma of the breast in an elderly patient: A rare case report. Mol Clin Oncol. 2017;7(4):609-14. https://doi.org/10.3892/mco.2017.1386.
https://doi.org/10.3892/mco.2017.1386...
,5555. Bae SY, Choi MY, Cho DH, Lee JE, Nam SJ, Yang JH. Mucinous carcinoma of the breast in comparison with invasive ductal carcinoma: clinicopathologic characteristics and prognosis. J Breast Cancer. 2011;14(4):308-13. https://doi.org/10.4048/jbc.2011.14.4.308.
https://doi.org/10.4048/jbc.2011.14.4.30...
) and these findings may suggest the importance of the aromatase enzyme and peripheral estrogens in the pathobiology of this carcinoma (3333. Honma N, Takubo K, Sawabe M, Arai T, Akiyama F, Sakamoto G, et al. Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years. Breast Cancer Res. 2009;11(4):R48. https://doi.org/10.1186/bcr2335
https://doi.org/10.1186/bcr2335...
).

A possible explanation for the lack of association between these results refers to the limitations of the studies evaluated, especially the lack of standardization of the primers, small samples and with different ethnicities, as well as insufficient time in the studies to observe significant effects.

CONCLUSIONS

This systematic review provides evidence that increased or decreased levels of CYP19A1 gene expression may be related to pathological clinical factors of disease, MFS, OS, DFS, WATi, markers of metabolic function, concentrations of E1, FSH, and in the use of multiple exons 1 of the CYP19A1 gene in breast cancer. However, there are a paucity of studies on the subject, mainly with larger samples, in Latin American women and in women with recurrence of breast cancer. Therefore, the elucidation of the CYP19A1 gene expression patterns may enable the characterization of women at high risk for breast cancer, as well as the development of strategies for prognosis and effective treatment, allowing better survival and reduction of disease progression.

ACKNOWLEDGMENTS

The authors thank the patients who participated in the current study and the Postgraduate Program of the Federal University of Piauí, Brazil.

REFERENCES

  • 1
    Limonta P, Moretti RM, Marzagalli M, Fontana F, Raimondi M, Montagnani Marelli M. Role of Endoplasmic Reticulum Stress in the Anticancer Activity of Natural Compounds. Int J Mol Sci. 2019;20(4):961. https://doi.org/10.3390/ijms20040961
    » https://doi.org/10.3390/ijms20040961
  • 2
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. https://doi.org/10.3322/caac.21492
    » https://doi.org/10.3322/caac.21492
  • 3
    Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piãeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-53. https://doi.org/10.1002/ijc.31937
    » https://doi.org/10.1002/ijc.31937
  • 4
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86. https://doi.org/10.1002/ijc.29210
    » https://doi.org/10.1002/ijc.29210
  • 5
    Costa-Silva DR, da Conceição Barros-Oliveira M, Borges RS, Campos-Verdes LM, da Silva-Sampaio JP, Escorcio-Dourado CS, et al. Insulin-like growth factor 1 gene polymorphism in women with breast cancer. Med Oncol. 2017;34(4):59. https://doi.org/10.1007/s12032-017-0915-4
    » https://doi.org/10.1007/s12032-017-0915-4
  • 6
    Campos-Verdes LM, da Silva-Sampaio JP, Costa-Silva DR, de Oliveira VA, Junior AMC, Silva VC, et al. Genetic polymorphism of calcium-sensing receptor in women with breast cancer. Med Oncol. 2018;35(3):23. https://doi.org/10.1007/s12032-018-1089-4
    » https://doi.org/10.1007/s12032-018-1089-4
  • 7
    Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269-75. https://doi.org/10.1002/cncr.29041
    » https://doi.org/10.1002/cncr.29041
  • 8
    Campos-Verdes LM, Costa-Silva DR, da Silva-Sampaio JP, Barros-Oliveira MDC, Escórcio-Dourado CS, Martins LM, et al. Review of Polymorphism of the Calcium-Sensing Receptor Gene and Breast Cancer Risk. Cancer Invest. 2018;36(2):1-7. https://doi.org/10.1080/07357907.2018.1430817
    » https://doi.org/10.1080/07357907.2018.1430817
  • 9
    Brown KA, Iyengar NM, Zhou XK, Gucalp A, Subbaramaiah K, Wang H, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-701. https://doi.org/10.1210/jc.2016-3606
    » https://doi.org/10.1210/jc.2016-3606
  • 10
    Tüzüner MB, Öztürk T, Eronat AP, Seyhan F, Kısakesen Hİ, Calay Z, et al. Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases. Biochem Genet. 2016;54(6):784-802. https://doi.org/10.1007/s10528-016-9756-7
    » https://doi.org/10.1007/s10528-016-9756-7
  • 11
    Friesenhengst A, Pribitzer-Winner T, Miedl H, Pröstling K, Schreiber M. Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer. Horm Cancer. 2018;9(2):128-38. https://doi.org/10.1007/s12672-017-0317-2
    » https://doi.org/10.1007/s12672-017-0317-2
  • 12
    Hong Y, Li H, Yuan YC, Chen S. Molecular characterization of aromatase. Ann N Y Acad Sci. 2009;1155:112-20. https://doi.org/10.1111/j.1749-6632.2009.03703.x
    » https://doi.org/10.1111/j.1749-6632.2009.03703.x
  • 13
    Chan HJ, Petrossian K, Chen S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J Steroid Biochem Mol Biol. 2016;161:73-83. https://doi.org/10.1016/j.jsbmb.2015.07.018
    » https://doi.org/10.1016/j.jsbmb.2015.07.018
  • 14
    Blackburn HL, Ellsworth DL, Shriver CD, Ellsworth RE. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy. Cancer Causes Control. 2015;26(3):319-32. https://doi.org/10.1007/s10552-014-0519-7
    » https://doi.org/10.1007/s10552-014-0519-7
  • 15
    Manna PR, Molehin D, Ahmed AU. Dysregulation of Aromatase in Breast, Endometrial, and Ovarian Cancers: An Overview of Therapeutic Strategies. Prog Mol Biol Transl Sci. 2016;144:487-537. https://doi.org/10.1016/bs.pmbts.2016.10.002
    » https://doi.org/10.1016/bs.pmbts.2016.10.002
  • 16
    Czajka-Oraniec I, Simpson ER. Aromatase research and its clinical significance. Endokrynol Pol. 2010;61(1):126-34.
  • 17
    To SQ, Knower KC, Cheung V, Simpson ER, Clyne CD. Transcriptional control of local estrogen formation by aromatase in the breast. J Steroid Biochem Mol Biol. 2015;145:179-86. https://doi.org/10.1016/j.jsbmb.2014.05.004
    » https://doi.org/10.1016/j.jsbmb.2014.05.004
  • 18
    Zhao H, Zhou L, Shangguan AJ, Bulun SE. Aromatase expression and regulation in breast and endometrial cancer. J Mol Endocrinol. 2016;57(1):R19-33. https://doi.org/10.1530/JME-15-0310
    » https://doi.org/10.1530/JME-15-0310
  • 19
    Holloway KR, Barbieri A, Malyarchuk S, Saxena M, Nedeljkovic-Kurepa A, Cameron Mehl M, et al. SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression. Mol Endocrinol. 2013;27(3):480-90. https://doi.org/10.1210/me.2012-1347
    » https://doi.org/10.1210/me.2012-1347
  • 20
    Kim HG, Jin SW, Kim YA, Khanal T, Lee GH, Kim SJ, et al. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells. Food Chem Toxicol. 2017;106(Pt A):232-241. https://doi.org/10.1016/j.fct.2017.05.058
    » https://doi.org/10.1016/j.fct.2017.05.058
  • 21
    Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SE. Regulation of breast cancer-associated aromatase promoters. Cancer Lett. 2009;273(1):15-27. https://doi.org/10.1016/j.canlet.2008.05.038
    » https://doi.org/10.1016/j.canlet.2008.05.038
  • 22
    Chand AL, Herridge KA, Howard TL, Simpson ER, Clyne CD. Tissue-specific regulation of aromatase promoter II by the orphan nuclear receptor LRH-1 in breast adipose stromal fibroblasts. Steroids. 2011;76(8):741-4. https://doi.org/10.1016/j.steroids.2011.02.024
    » https://doi.org/10.1016/j.steroids.2011.02.024
  • 23
    Fukami M, Suzuki J, Nakabayashi K, Tsunashima R, Ogata T, Shozu M, et al. Lack of genomic rearrangements involving the aromatase gene CYP19A1 in breast cancer. Breast Cancer. 2014;21(3):382-5. https://doi.org/10.1007/s12282-013-0471-5
    » https://doi.org/10.1007/s12282-013-0471-5
  • 24
    Wang X, Simpson ER, Brown KA. Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer. J Steroid Biochem Mol Biol. 2015;153:35-44. https://doi.org/10.1016/j.jsbmb.2015.07.008
    » https://doi.org/10.1016/j.jsbmb.2015.07.008
  • 25
    Hong Y, Li H, Ye J, Miki Y, Yuan YC, Sasano H, et al. Epitope characterization of an aromatase monoclonal antibody suitable for the assessment of intratumoral aromatase activity. PLoS One. 2009;4(11):e8050. https://doi.org/10.1371/journal.pone.0008050
    » https://doi.org/10.1371/journal.pone.0008050
  • 26
    Dunbier AK, Hong Y, Masri S, Brown KA, Sabnis GJ, Palomares MR. Progress in aromatase research and identification of key future directions. J Steroid Biochem Mol Biol. 2010;118(4-5):311-315. https://doi.org/10.1016/j.jsbmb.2009.09.005
    » https://doi.org/10.1016/j.jsbmb.2009.09.005
  • 27
    Sjoquist KM, Martyn J, Edmondson RJ, Friedlander ML. The role of hormonal therapy in gynecological cancers-current status and future directions. Int J Gynecol Cancer. 2011;21(7):1328-33. https://doi.org/10.1097/IGC.0b013e31821d6021
    » https://doi.org/10.1097/IGC.0b013e31821d6021
  • 28
    Mukhopadhyay KD, Liu Z, Bandyopadhyay A, Kirma NB, Tekmal RR, Wang S, et al. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells. PLoS One. 2015;10(4):e0121136. https://doi.org/10.1371/journal.pone.0121136
    » https://doi.org/10.1371/journal.pone.0121136
  • 29
    Xu YC, Zhang FC, Li JJ, Dai JQ, Liu Q, Tang L, et al. RRM1, TUBB3, TOP2A, CYP19A1, CYP2D6: Difference between mRNA and protein expression in predicting prognosis of breast cancer patients. Oncol Rep. 2015;34(4):1883-94. https://doi.org/10.3892/or.2015.4183
    » https://doi.org/10.3892/or.2015.4183
  • 30
    Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. https://doi.org/10.1136/bmj.b2535
    » https://doi.org/10.1136/bmj.b2535
  • 31
    Bollet MA, Savignoni A, De Koning L, Tran-Perennou C, Barbaroux C, Degeorges A, et al. Tumor aromatase expression as a prognostic factor for local control in young breast cancer patients after breast-conserving treatment. Breast Cancer Res. 2009;11(4):R54. https://doi.org/10.1186/bcr2343
    » https://doi.org/10.1186/bcr2343
  • 32
    Savolainen-Peltonen H, Vihma V, Wang F, Turpeinen U, Hämäläinen E, Haanpää M, et al. Estrogen biosynthesis in breast adipose tissue during menstrual cycle in women with and without breast cancer. Gynecol Endocrinol. 2018;34(12):1039-43. https://doi.org/10.1080/09513590.2018.1474868
    » https://doi.org/10.1080/09513590.2018.1474868
  • 33
    Honma N, Takubo K, Sawabe M, Arai T, Akiyama F, Sakamoto G, et al. Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years. Breast Cancer Res. 2009;11(4):R48. https://doi.org/10.1186/bcr2335
    » https://doi.org/10.1186/bcr2335
  • 34
    Patel S. Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review. J Steroid Biochem Mol Biol. 2017;168:19-25. https://doi.org/10.1016/j.jsbmb.2017.01.009
    » https://doi.org/10.1016/j.jsbmb.2017.01.009
  • 35
    Kidokoro K, Ino K, Hirose K, Kajiyama H, Hosono S, Suzuki T, et al. Association between CYP19A1 polymorphisms and sex hormones in postmenopausal Japanese women. J Hum Genet. 2009;54(2):78-85. https://doi.org/10.1038/jhg.2008.11
    » https://doi.org/10.1038/jhg.2008.11
  • 36
    Germain D. Estrogen carcinogenesis in breast cancer. Endocrinol Metab Clin North Am. 2011;40(3):473-84, vii. https://doi.org/10.1016/j.ecl.2011.05.009
    » https://doi.org/10.1016/j.ecl.2011.05.009
  • 37
    Salhab M, Reed MJ, Al Sarakbi W, Jiang WG, Mokbel K. The role of aromatase and 17-beta-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast câncer. Breast Cancer Res Treat. 2006;99(2):155-62. https://doi.org/10.1007/s10549-006-9198-8
    » https://doi.org/10.1007/s10549-006-9198-8
  • 38
    Miyoshi Y, Ando A, Hasegawa S, Ishitobi M, Taguchi T, Tamaki Y, et al. High expression of steroid sulfatase mRNA predicts poor prognosis in patients with estrogen receptor-positive breast cancer. Clin Cancer Res. 2003;9(6):2288-93.
  • 39
    Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, et al. Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast. Breast Cancer Res. 2003;5(6):R250-6. https://doi.org/10.1186/bcr657
    » https://doi.org/10.1186/bcr657
  • 40
    Licznerska BE, Wegman PP, Nordenskjöld B, Wingren S. In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients. Breast Cancer Res Treat. 2008;112(1):15-23. https://doi.org/10.1007/s10549-007-9819-x
    » https://doi.org/10.1007/s10549-007-9819-x
  • 41
    Girault I, Lerebours F, Tozlu S, Spyratos F, Tubiana-Hulin M, Lidereau R, et al. Real-time reverse transcription PCR assay of CYP19 expression: application to a well-defined series of post-menopausal breast carcinomas. J Steroid Biochem Mol Biol. 2002;82(4-5):323-32. https://doi.org/10.1016/S0960-0760(02)00190-5
    » https://doi.org/10.1016/S0960-0760(02)00190-5
  • 42
    Sutton-Tyrrell K, Zhao X, Santoro N, Lasley B, Sowers M, Johnston J, et al. Reproductive hormones and obesity: 9 years of observation from the Study of Women's Health Across the Nation. Am J Epidemiol. 2010;171(11):1203-13. https://doi.org/10.1093/aje/kwq049
    » https://doi.org/10.1093/aje/kwq049
  • 43
    Gibson CJ, Thurston RC, El Khoudary SR, Sutton-Tyrrell K, Matthews KA. Body mass index following natural menopause and hysterectomy with and without bilateral oophorectomy. Int J Obes (Lond). 2013;37(6):809-13.
  • 44
    Iyengar NM, Morris PG, Zhou XK, Gucalp A, Giri D, Harbus MD, et al. Menopause is a determinant of breast adipose inflammation. Cancer Prev Res (Phila). 2015;8(5):349-58. https://doi.org/10.1158/1940-6207
    » https://doi.org/10.1158/1940-6207
  • 45
    Simpson ER, Brown KA. Obesity and breast cancer: role of inflammation and aromatase. J Mol Endocrinol. 2013;51(3):T51-9. https://doi.org/10.1530/JME-13-0217
    » https://doi.org/10.1530/JME-13-0217
  • 46
    Sasano H, Miki Y, Nagasaki S, Suzuki T. In situ estrogen production and its regulation in human breast carcinoma: from endocrinology to intracrinology. Pathol Int. 2009;59(11):777-89. https://doi.org/10.1111/j.1440-1827.2009.02444.x
    » https://doi.org/10.1111/j.1440-1827.2009.02444.x
  • 47
    Surekha D, Sailaja K, Rao DN, Padma T, Raghunadharao D, Vishnupriya S. Association of CYP19 polymorphisms with breast cancer risk: A case-control study. J Nat Sci Biol Med. 2014;5(2):250-4. https://doi.org/10.4103/0976-9668.136150
    » https://doi.org/10.4103/0976-9668.136150
  • 48
    Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276-85. https://doi.org/10.1056/NEJM200101253440407
    » https://doi.org/10.1056/NEJM200101253440407
  • 49
    Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Res. 2005;7(3):131-42. https://doi.org/10.1186/bcr1029
    » https://doi.org/10.1186/bcr1029
  • 50
    Britt K, Ashworth A, Smalley M. Pregnancy and the risk of breast cancer. Endocr Relat Cancer. 2007;14(4):907-33. https://doi.org/10.1677/ERC-07-0137
    » https://doi.org/10.1677/ERC-07-0137
  • 51
    Yoshimura N, Harada N, Bukholm I, Kåresen R, Børresen-Dale AL, Kristensen VN. Intratumoural mRNA expression of genes from the oestradiol metabolic pathway and clinical and histopathological parameters of breast cancer. Breast Cancer Res. 2004;6(2):R46-55. https://doi.org/10.1186/bcr746
    » https://doi.org/10.1186/bcr746
  • 52
    Stocco C. Aromatase expression in the ovary: hormonal and molecular regulation. Steroids. 2008;73(5):473-87. https://doi.org/10.1016/j.steroids.2008.01.017
    » https://doi.org/10.1016/j.steroids.2008.01.017
  • 53
    Parakh TN, Hernandez JA, Grammer JC, Weck J, Hunzicker-Dunn M, Zeleznik AJ, et al. Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin. Proc Natl Acad Sci U S A. 2006;103(33):12435-40. https://doi.org/10.1073/pnas.0603006103
    » https://doi.org/10.1073/pnas.0603006103
  • 54
    Takuwa H, Tsuji W, Yotsumoto F. Palliative surgery for giant mucinous carcinoma of the breast in an elderly patient: A rare case report. Mol Clin Oncol. 2017;7(4):609-14. https://doi.org/10.3892/mco.2017.1386
    » https://doi.org/10.3892/mco.2017.1386
  • 55
    Bae SY, Choi MY, Cho DH, Lee JE, Nam SJ, Yang JH. Mucinous carcinoma of the breast in comparison with invasive ductal carcinoma: clinicopathologic characteristics and prognosis. J Breast Cancer. 2011;14(4):308-13. https://doi.org/10.4048/jbc.2011.14.4.308
    » https://doi.org/10.4048/jbc.2011.14.4.308

Publication Dates

  • Publication in this collection
    14 June 2021
  • Date of issue
    2021

History

  • Received
    6 Feb 2021
  • Accepted
    6 May 2021
Creative Common - by 4.0
This is an Open Access article distributed under the terms of the Creative Commons License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.
Faculdade de Medicina / USP Rua Dr Ovídio Pires de Campos, 225 - 6 and., 05403-010 São Paulo SP - Brazil, Tel.: (55 11) 2661-6235 - São Paulo - SP - Brazil
E-mail: clinics@hc.fm.usp.br