Cross-talk of Androgen & Cytokine Signalling in Breast Cancer

Abstract

Introduction: Breast cancer progression is strongly influenced by the tumor microenvironment, where inflammatory cytokines and androgen receptor (AR) signaling regulate tumor growth, immune responses, and disease progression. Understanding the interaction between cytokines and AR signaling may provide novel therapeutic strategies.

Aim & Objective: To investigate the effects of inflammatory cytokines and dihydrotestosterone (DHT) on breast cancer cell proliferation, AR signaling, inflammatory pathways, immune modulation, and tumor progression using in vitro and in vivo models.

Materials & Methods: MCF-7 breast cancer cells were treated with IL-6, IL-10, TNF-α, and DHT to evaluate cell proliferation, AR signaling, and inflammatory gene expression. The involvement of the JAK/STAT pathway was examined using the inhibitor AG490. In vivo, mouse mammary tumor and 4T1 tumor models were used to assess inflammatory responses, tumor growth, and immune cell populations following DHT and bicalutamide treatment.

Results: IL-6 significantly enhanced MCF-7 cell proliferation and upregulated AR, prostate-specific antigen (PSA), and p21 expression in a dose- and time-dependent manner, whereas IL-10 inhibited these effects. AG490 abolished IL-6-induced AR activation, confirming STAT3-dependent signaling. DHT suppressed TNF-α production, modulated inflammatory mediators, and differentially regulated cytokine expression. In vivo, DHT attenuated lipopolysaccharide-induced inflammation through AR signaling, while bicalutamide reversed these effects. Bicalutamide significantly reduced 4T1 tumor growth, whereas DHT produced modest tumor regression and increased splenic CD8⁺, CD4⁺, and regulatory T-cell populations.

Conclusion: Cytokine-mediated AR signaling plays a pivotal role in breast cancer progression and immune regulation. Targeting AR-associated inflammatory pathways may offer a promising therapeutic approach for breast cancer.

References

1. Hall RE, Birrell SN, Tilley WD, Sutherland RL. Expression of the androgen receptor and an androgen-responsive protein, apolipoprotein D, in human breast cancer. Br J Cancer. 1996;74(8):1175-1180. doi:10.1038/bjc.1996.513.
2. Kuenen-Boumeester V, van der Kwast TH, Claassen CC, et al. The clinical significance of androgen receptors in breast cancer and their relation to histological and cell biological parameters. Eur J Cancer. 1996;32A(9):1560-1565. doi:10.1016/0959-8049(96)00112-8.
3. Isola JJ. Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol. 1993;170(1):31-35. doi:10.1002/path.1711700106.
4. Park S, Koo J, Park HS, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol. 2010;21(3):488-492. doi:10.1093/annonc/mdp510.
5. Søreide JA, Lea OA, Varhaug JE, et al. Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, prognostic factors and predictive value for adjuvant tamoxifen. Eur J Surg Oncol. 1992;18(2):112-118.
6. Suzuki T, Miki Y, Nakamura Y, et al. Androgens in human breast carcinoma. Med Mol Morphol. 2010;43(2):75-81. doi:10.1007/s00795-010-0494-3.
7. Gucalp A, Traina TA. Triple-negative breast cancer: role of the androgen receptor. Cancer J. 2010;16(1):62-65. doi:10.1097/PPO.0b013e3181ce4ae1.
8. Nahleh Z. Androgen receptor as a target for the treatment of hormone receptor-negative breast cancer: an uncharted territory. Future Oncol. 2008;4(1):15-21. doi:10.2217/14796694.4.1.15.
9. Fioretti FM, Sita-Lumsden A, Bevan CL, Brooke GN. Revising the role of the androgen receptor in breast cancer. J Mol Endocrinol. 2014;52(3):257-265. doi:10.1530/JME-14-0030.
10. Agoff SN, Swanson PE, Linden H, et al. Androgen receptor expression in estrogen receptor-negative breast cancer: immunohistochemical, clinical, and prognostic associations. Am J Clin Pathol. 2003;120(5):725-731. doi:10.1309/42F0-0D0D-JD0J-5EDT.
11. Moinfar F, Okcu M, Tsybrovskyy O, et al. Androgen receptors frequently are expressed in breast carcinomas: potential relevance to new therapeutic strategies. Cancer. 2003;98(4):703-711. doi:10.1002/cncr.11532.
12. Micello D, Marando A, Sahnane N, et al. Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers. Virchows Arch. 2010;457(4):467-476. doi:10.1007/s00428-010-0964-y.
13. Ogawa Y, Hai E, Matsumoto K, et al. Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers. Int J Clin Oncol. 2008;13(5):431-435. doi:10.1007/s10147-008-0770-6.
14. Kuenen-Boumeester V, Claassen CC, van der Kwast TH, et al. Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer. Int J Cancer. 1992;52(4):581-584. doi:10.1002/ijc.2910520415.
15. McGhan LJ, McCullough AE, Protheroe CA, et al. Androgen receptor-positive triple-negative breast cancer: a unique breast cancer subtype. Ann Surg Oncol. 2014;21(2):361-367. doi:10.1245/s10434-013-3260-7.
16. Bayer-Garner IB, Smoller B. Androgen receptors: a marker to increase sensitivity for identifying breast cancer in skin metastasis of unknown primary site. Mod Pathol. 2000;13(2):119-122. doi:10.1038/modpathol.3880021.
17. Lea OA, Kvinnsland S, Thorsen T. Improved measurement of androgen receptors in human breast cancer. Cancer Res. 1989;49(24 Pt 1):7162-7167.
18. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res. 2013;19(19):5505-5512. doi:10.1158/1078-0432.CCR-12-3327.
19. Luo X, Shi YX, Li ZM, et al. Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer. 2010;29(6):585-590. doi:10.5732/cjc.009.10673.
20. Loibl S, Müller BM, von Minckwitz G, et al. Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat. 2011;130(2):477-487. doi:10.1007/s10549-011-1715-8.
21. Castellano I, Allia E, Accortanzo V, et al. Androgen receptor expression is a significant prognostic factor in estrogen receptor-positive breast cancers. Breast Cancer Res Treat. 2010;124(3):607-617. doi:10.1007/s10549-010-0761-y.
22. Schippinger W, Regitnig P, Dandachi N, et al. Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer. Virchows Arch. 2006;449(1):24-30. doi:10.1007/s00428-006-0213-6.
23. Søiland H, Korner H, Varhaug JE, et al. Prognostic relevance of androgen receptor detection in operable breast cancer. J Surg Oncol. 2008;98(7):551-558. doi:10.1002/jso.21156.
24. Hu R, Dawood S, Holmes MD, et al. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867-1874. doi:10.1158/1078-0432.CCR-10-2021.
25. Park S, Koo JS, Kim MS, et al. Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers. Ann Oncol. 2011;22(8):1755-1762. doi:10.1093/annonc/mdq678.
26. Peters AA, Buchanan G, Ricciardelli C, et al. Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res. 2009;69(15):6131-6140. doi:10.1158/0008-5472.CAN-09-0452.
27. Doane AS, Danso M, Lal P, et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006;25(28):3994-4008. doi:10.1038/sj.onc.1209415.
28. Tsang JYS, Ni YB, Chan SK, et al. Androgen receptor expression shows distinctive significance in ER-positive and ER-negative breast cancers. Ann Surg Oncol. 2014;21(7):2218-2228. doi:10.1245/s10434-014-3629-2.
29. Mrklić I, Pogorelić Z, Čapkun V, et al. Expression of androgen receptors in triple-negative breast carcinomas. Acta Histochem. 2013;115(4):344-348. doi:10.1016/j.acthis.2012.09.006.
30. Robinson JLL, MacArthur S, Ross-Innes CS, et al. Androgen receptor-driven transcription in molecular apocrine breast cancer is mediated by FoxA1. EMBO J. 2011;30(15):3019-3027. doi:10.1038/emboj.2011.216.
31. Sutton LM, Cao D, Sarode V, et al. Decreased androgen receptor expression is associated with distant metastases in androgen receptor-expressing triple-negative breast carcinoma. Am J Clin Pathol. 2012;138(4):511-516. doi:10.1309/AJCP8AVF8FDPTZLH.
32. Tang D, Xu S, Zhang Q, et al. The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer. Med Oncol. 2012;29(2):526-533. doi:10.1007/s12032-011-9948-2.
33. Karrer-Voegeli S, Rey F, Reymond MJ, et al. Androgen dependence of hirsutism, acne, and alopecia in women. Medicine (Baltimore). 2009;88(1):32-45. doi:10.1097/MD.0b013e3181946a2c.
34. Papadatos-Pastos D, de Bono JS, Kaye SB. Revisiting the role of antiandrogen strategies in ovarian cancer. Oncologist. 2011;16(10):1413-1421. doi:10.1634/theoncologist.2011-0164.
35. Sweet MJ, Hume DA. Endotoxin signal transduction in macrophages. J Leukoc Biol. 1996;60(1):8-26. doi:10.1002/jlb.60.1.8.
36. Doyle SL, O'Neill LAJ. Toll-like receptors: from the discovery of NF-κB to new insights into transcriptional regulation in innate immunity. Biochem Pharmacol. 2006;72(9):1102-1113. doi:10.1016/j.bcp.2006.07.010.
37. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-376. doi:10.1146/annurev.immunol.21.120601.141126.