Palabras clave
cáncer de seno
receptor de andrógenos
receptor de estrógenos
proliferación celular
subtipos moleculares
receptor de andrógenos
receptor de estrógenos
proliferación celular
subtipos moleculares
Cómo citar
Rangel, N., Aristizábal, A. F., & Rondón, M. (2019). Expresión del receptor de andrógenos relativa al receptor de estrógenos (AR/ER) y su correlación con una señal génica de proliferación en cáncer de seno ER-positivo. Revista Colombiana De Endocrinología, Diabetes &Amp; Metabolismo, 6(3), 164–169. https://doi.org/10.53853/encr.6.3.530
Resumen
Objetivo: previamente se reportó que tumores de seno con proporción receptor de andrógenos/receptor de estrógenos ?2 (AR/ER ?2) se asocian con peores pronósticos. De acuerdo con lo anterior, el objetivo del presente estudio fue evaluar la relación entre la proporción AR/ER y una señal génica de proliferación celular en cáncer de seno (CS; también conocido como cáncer de mama) ER positivo (ER+).
Métodos: se obtuvieron 1093 muestras de CS primario con datos de expresión génica de la base de datos pública NCI Genomic Data Commons. Se ejecutaron análisis bioinformáticos para establecer niveles de expresión génica de AR y ER, así como de los marcadores de proliferación AURKb, BUB1B, BUB1, CDK1 y CHEK1. Adicionalmente, se definieron subtipos moleculares de CS utilizando el bioclasificador PAM50.
Resultados: 835 casos se reportaron como ER+. Entre estos, 58 tumores (7%) presentaron mayores niveles de expresión de AR respecto a ER (AR/ER ?2). En dichos casos se observaron niveles significativamente más altos de proliferación con respecto a tumores, con proporción AR/ER <2 (p = 0,02), y preferencialmente se clasificaron dentro de los subtipos moleculares luminal B y HER2 enriquecido (76,5%).
Conclusión: nuestros resultados confirman reportes previos y sugieren que los casos de CS con proporción AR/ER ?2 se asocian con tumores que tienen un comportamiento biológico más agresivo. Asimismo, se refuerza la idea de utilizar inhibidores de AR para el tratamiento de pacientes con CS ER+ que presentan altos niveles de expresión de este tipo de cáncer
Citas
1. Early Breast Cancer Trialists’ Collaborative Group, Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patientlevel meta-analysis of randomised trials. Lancet. 2011;378(9793):771-84.
2. Hu R, Dawood S, Holmes M, Collins L, Schnitt S, Cole K, et al. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867-74.
3. Park S, Koo J, Park H, Kim J, Choi S, Lee J, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol. 2010;21(3):488-92.
4. Aleskandarany M, Abduljabbar R, Ashankyty I, Elmouna A, Jerjees D, Ali S, et al. Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis. Breast Cancer Res Treat. 2016;159(2):215-27.
5. Bozovic-Spasojevic I, Zardavas D, Brohee S, Ameye L, Fumagalli D, Ades F, et al. The prognostic role of androgen receptor in patients with early-stage breast cancer: a meta-analysis of clinical and gene expression data. Clin Cancer Res. 2017;23(11):2702-12.
6. Castellano I, Allia E, Accortanzo V, Vandone A, Chiusa L, Arisio R, et al. Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res Treat. 2010;124(3):607-17.
7. Niemeier L, Dabbs J, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23(2):205-12.
8. Asano Y, Kashiwagi S, Goto W, Tanaka S, Morisaki T, Takashima T, et al. Expression and clinical significance of androgen receptor in triple-negative breast cancer. Cancers (Basel). 2017;9(1).
9. Hilborn E, Gacic J, Fornander T, Nordenskjold B, Stal O, Jansson A. Androgen receptor expression predicts beneficial tamoxifen response in estrogen receptor-alpha-negative breast cancer. Br J Cancer. 2016;114(3):248-55.
10. Jiang H, Kuang X, Sun W, Xu Y, Zheng Y, Liu Y, et al. Androgen receptor expression predicts different clinical outcomes for breast cancer patients stratified by hormone receptor status. Oncotarget. 2016;7(27):41285-93.
11. Luo X, Shi Y, Li Z, Jiang W. Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer. 2010;29(6):585-90.
12. Pistelli M, Caramanti M, Biscotti T, Santinelli A, Pagliacci A, De Lisa M, et al. Androgen receptor expression in early triple-negative breast cancer: clinical significance and prognostic associations. Cancers (Basel). 2014;6(3):1351-62.
13. Qu Q, Mao Y, Fei X, Shen K. The impact of androgen receptor expression on breast cancer survival: a retrospective study and meta-analysis. PLoS One. 2013;8(12):e82650.
14. Vera-Badillo F, Templeton A, de Gouveia P, Diaz-Padilla I, Bedard P, AlMubarak M, et al. Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(1):djt319.
15. Peters A, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM, et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res. 2009;69(15):6131-40.
16. Cops E, Bianco-Miotto T, Moore N, Clarke C, Birrell S, Butler L, et al. Antiproliferative actions of the synthetic androgen, mibolerone, in breast cancer cells are mediated by both androgen and progesterone receptors. J Steroid Biochem Mol Biol. 2008;110(3-5):236-43.
17. Greeve M, Allan R, Harvey J, Bentel J. Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1). J Mol Endocrinol. 2004;32(3):793-810.
18. Macedo L, Guo Z, Tilghman S, Sabnis G, Qiu Y, Brodie A. Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res. 2006;66(15):7775-82.
19. Need E, Selth L, Harris T, Birrell S, Tilley W, Buchanan G. Research resource: interplay between the genomic and transcriptional networks of androgen receptor and estrogen receptor alpha in luminal breast cancer cells. Mol Endocrinol. 2012;26(11):1941-52.
20. Buchanan G, Birrell S, Peters A, Bianco-Miotto T, Ramsay K, Cops E, et al. Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate. Cancer Res. 2005;65(18):8487-96.
21. Birrell S, Bentel J, Hickey T, Ricciardelli C, Weger M, Horsfall D, et al. Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol. 1995;52(5):459-67.
22. Lin H, Sun M, Lin C, Tang H, London D, Shih A, et al. Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-alpha-positive and -negative breast cancer cells. J Steroid Biochem Mol Biol. 2009;113(3-5):182-8.
23. Lehmann B, Bauer J, Chen X, Sanders M, Chakravarthy A, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-67.
24. Robinson J, Macarthur S, Ross-Innes C, Tilley W, Neal D, Mills I, et al. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 2011;30(15):3019-27.
25. Cochrane D, Bernales S, Jacobsen B, Cittelly D, Howe E, D’Amato N, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 2014;16(1):R7.
26. Rangel N, Rondon-Lagos M, Annaratone L, Osella-Abate S, Metovic J, Mano M, et al. The role of the AR/ER ratio in ER-positive breast cancer patients. Endocr Relat Cancer. 2018;25(3):163-72.
27. Iwamoto T, Booser D, Valero V, Murray J, Koenig K, Esteva F, et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. J Clin Oncol. 2012;30(7):729-34.
28. van ‘t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-6.
29. Parker J, Mullins M, Cheang M, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-7.
30. Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCG Abiolinks: a R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44(8):e71.
31. Team RC. R: a language and environment for statistical computing Vienna, Austria: R Foundation for Statistical Computing; 2016. Disponible en:
https://www.R-project.org/
32. Liao Y, Xia X, Liu N, Cai J, Guo Z, Li Y, et al. Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination. Oncogene. 2018;37(14):1896-910.
33. De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, et al. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 2010;121(1):1-11.
34. Yu Q, Niu Y, Liu N, Zhang J, Liu T, Zhang R, et al. Expression of androgen receptor in breast cancer and its significance as a prognostic factor. Ann Oncol. 2011;22(6):1288-94.
35. Grogg A, Trippel M, Pfaltz K, Ladrach C, Droeser R, Cihoric N, et al. Androgen receptor status is highly conserved during tumor progression of breast cancer. BMC Cancer. 2015;15:872.
36. Hanley K, Wang J, Bourne P, Yang Q, Gao A, Lyman G, et al. Lack of expression of androgen receptor may play a critical role in transformation from in situ to invasive basal subtype of high-grade ductal carcinoma of the breast. Hum Pathol. 2008;39(3):386-92.
37. Feng J, Li L, Zhang N, Liu J, Zhang L, Gao H, et al. Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms. Oncogene. 2017;36(20):2775-90.
38. Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794-803.
39. Al-Zahrani K, Cook D, Vanderhyden B, Sabourin L. Assessing the efficacy of androgen receptor and Sox10 as independent markers of the triplenegative breast cancer subtype by transcriptome profiling. Oncotarget. 2018;9(70):33348-59.
40. Daemen A, Manning G. HER2 is not a cancer subtype but rather a pancancer event and is highly enriched in AR-driven breast tumors. Breast Cancer Res. 2018;20(1):8.
41. Chia K, Liu J, Francis G, Naderi A. A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia. 2011;13(2):154-66.
2. Hu R, Dawood S, Holmes M, Collins L, Schnitt S, Cole K, et al. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867-74.
3. Park S, Koo J, Park H, Kim J, Choi S, Lee J, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol. 2010;21(3):488-92.
4. Aleskandarany M, Abduljabbar R, Ashankyty I, Elmouna A, Jerjees D, Ali S, et al. Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis. Breast Cancer Res Treat. 2016;159(2):215-27.
5. Bozovic-Spasojevic I, Zardavas D, Brohee S, Ameye L, Fumagalli D, Ades F, et al. The prognostic role of androgen receptor in patients with early-stage breast cancer: a meta-analysis of clinical and gene expression data. Clin Cancer Res. 2017;23(11):2702-12.
6. Castellano I, Allia E, Accortanzo V, Vandone A, Chiusa L, Arisio R, et al. Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res Treat. 2010;124(3):607-17.
7. Niemeier L, Dabbs J, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23(2):205-12.
8. Asano Y, Kashiwagi S, Goto W, Tanaka S, Morisaki T, Takashima T, et al. Expression and clinical significance of androgen receptor in triple-negative breast cancer. Cancers (Basel). 2017;9(1).
9. Hilborn E, Gacic J, Fornander T, Nordenskjold B, Stal O, Jansson A. Androgen receptor expression predicts beneficial tamoxifen response in estrogen receptor-alpha-negative breast cancer. Br J Cancer. 2016;114(3):248-55.
10. Jiang H, Kuang X, Sun W, Xu Y, Zheng Y, Liu Y, et al. Androgen receptor expression predicts different clinical outcomes for breast cancer patients stratified by hormone receptor status. Oncotarget. 2016;7(27):41285-93.
11. Luo X, Shi Y, Li Z, Jiang W. Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer. 2010;29(6):585-90.
12. Pistelli M, Caramanti M, Biscotti T, Santinelli A, Pagliacci A, De Lisa M, et al. Androgen receptor expression in early triple-negative breast cancer: clinical significance and prognostic associations. Cancers (Basel). 2014;6(3):1351-62.
13. Qu Q, Mao Y, Fei X, Shen K. The impact of androgen receptor expression on breast cancer survival: a retrospective study and meta-analysis. PLoS One. 2013;8(12):e82650.
14. Vera-Badillo F, Templeton A, de Gouveia P, Diaz-Padilla I, Bedard P, AlMubarak M, et al. Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(1):djt319.
15. Peters A, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM, et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res. 2009;69(15):6131-40.
16. Cops E, Bianco-Miotto T, Moore N, Clarke C, Birrell S, Butler L, et al. Antiproliferative actions of the synthetic androgen, mibolerone, in breast cancer cells are mediated by both androgen and progesterone receptors. J Steroid Biochem Mol Biol. 2008;110(3-5):236-43.
17. Greeve M, Allan R, Harvey J, Bentel J. Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1). J Mol Endocrinol. 2004;32(3):793-810.
18. Macedo L, Guo Z, Tilghman S, Sabnis G, Qiu Y, Brodie A. Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res. 2006;66(15):7775-82.
19. Need E, Selth L, Harris T, Birrell S, Tilley W, Buchanan G. Research resource: interplay between the genomic and transcriptional networks of androgen receptor and estrogen receptor alpha in luminal breast cancer cells. Mol Endocrinol. 2012;26(11):1941-52.
20. Buchanan G, Birrell S, Peters A, Bianco-Miotto T, Ramsay K, Cops E, et al. Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate. Cancer Res. 2005;65(18):8487-96.
21. Birrell S, Bentel J, Hickey T, Ricciardelli C, Weger M, Horsfall D, et al. Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol. 1995;52(5):459-67.
22. Lin H, Sun M, Lin C, Tang H, London D, Shih A, et al. Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-alpha-positive and -negative breast cancer cells. J Steroid Biochem Mol Biol. 2009;113(3-5):182-8.
23. Lehmann B, Bauer J, Chen X, Sanders M, Chakravarthy A, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-67.
24. Robinson J, Macarthur S, Ross-Innes C, Tilley W, Neal D, Mills I, et al. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 2011;30(15):3019-27.
25. Cochrane D, Bernales S, Jacobsen B, Cittelly D, Howe E, D’Amato N, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 2014;16(1):R7.
26. Rangel N, Rondon-Lagos M, Annaratone L, Osella-Abate S, Metovic J, Mano M, et al. The role of the AR/ER ratio in ER-positive breast cancer patients. Endocr Relat Cancer. 2018;25(3):163-72.
27. Iwamoto T, Booser D, Valero V, Murray J, Koenig K, Esteva F, et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. J Clin Oncol. 2012;30(7):729-34.
28. van ‘t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-6.
29. Parker J, Mullins M, Cheang M, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-7.
30. Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCG Abiolinks: a R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44(8):e71.
31. Team RC. R: a language and environment for statistical computing Vienna, Austria: R Foundation for Statistical Computing; 2016. Disponible en:
https://www.R-project.org/
32. Liao Y, Xia X, Liu N, Cai J, Guo Z, Li Y, et al. Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination. Oncogene. 2018;37(14):1896-910.
33. De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, et al. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 2010;121(1):1-11.
34. Yu Q, Niu Y, Liu N, Zhang J, Liu T, Zhang R, et al. Expression of androgen receptor in breast cancer and its significance as a prognostic factor. Ann Oncol. 2011;22(6):1288-94.
35. Grogg A, Trippel M, Pfaltz K, Ladrach C, Droeser R, Cihoric N, et al. Androgen receptor status is highly conserved during tumor progression of breast cancer. BMC Cancer. 2015;15:872.
36. Hanley K, Wang J, Bourne P, Yang Q, Gao A, Lyman G, et al. Lack of expression of androgen receptor may play a critical role in transformation from in situ to invasive basal subtype of high-grade ductal carcinoma of the breast. Hum Pathol. 2008;39(3):386-92.
37. Feng J, Li L, Zhang N, Liu J, Zhang L, Gao H, et al. Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms. Oncogene. 2017;36(20):2775-90.
38. Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794-803.
39. Al-Zahrani K, Cook D, Vanderhyden B, Sabourin L. Assessing the efficacy of androgen receptor and Sox10 as independent markers of the triplenegative breast cancer subtype by transcriptome profiling. Oncotarget. 2018;9(70):33348-59.
40. Daemen A, Manning G. HER2 is not a cancer subtype but rather a pancancer event and is highly enriched in AR-driven breast tumors. Breast Cancer Res. 2018;20(1):8.
41. Chia K, Liu J, Francis G, Naderi A. A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia. 2011;13(2):154-66.
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