Expression of androgen receptor in breast cancer & its correlation with other steroid receptors & growth factors

Breast carcinoma is the most common malignancy among females globally. Approximately, 1.15 million new cases of breast cancer accounting for nearly one fourth of all malignancies are diagnosed among women worldwide1. Earlier, the reported incidence of breast cancer in Asian and African countries was on the lower side, but the recent estimates exhibit an upward trend in the incidence2. The population based cancer registry programme in India, reveals breast cancer as the commonest cancer among women in Mumbai and Delhi, whereas in Chennai and Bangalore, it is listed as the second most leading site of cancer3. In India, about 80,000 new cases of breast cancer were diagnosed during the year 20014,5. Locally advanced breast cancer (LABC) approximately constitutes more than half of all the breast cancer cases6 and are managed by neoadjuvant chemotherapy (NACT) in addition to surgery for both local and systemic control. Due to hormonal changes at puberty, the ductal epithelial cells transform and develop the potential for proliferation and differentiation. Proliferation of these cells is triggered by the steroid hormones released from ovaries or by exogenously administered hormones. Steroid hormones stimulate breast cell proliferation by binding to their respective receptors, resulting in the clonal propagation of normal as well as tumour cells, with nucleotide sequence error or spontaneous errors in DNA replication. While such signals may directly affect steroid hormone receptor-positive cells, these also induce release of growth factors that act indirectly upon receptor-negative cells7. The nuclear superfamily of steroid receptors includes estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and vitamin D receptor, and of these, the role of ER and PR in human breast cancer has been extensively studied. AR is known to have a role in normal prostate development and progression of prostate cancer, but it has also been reported to be involved in differentiation, development and regulation of breast cell growth8,9. Androgens may influence breast cancer risk indirectly through their conversion to estradiol or by competing for steroid binding proteins, or directly by binding to the AR10. Among post-menopausal women, circulating androgen levels appear to be positively associated with breast cancer risk, but it is not known whether these effects are mediated through AR. AR positive breast cancer patients have been reported to have prolonged survival and a better response to hormonal treatment than AR negative patients10. It has been shown that AR expression correlates well with ER expression, but more so with PR expression11. Hence the co-expression status of receptors may identify more accurately those patients with breast cancer who are most likely to respond to hormonal treatment11. Androgens (testosterone/DHEA) are known to exert their action by increasing the expression of EGFR (epidermal growth factor receptors) and are regarded as a marker of poor prognosis. In addition, CD105 (endoglin) is a hypoxia-inducible protein acting as a receptor for the transforming growth factor beta (TGFβ) family of growth factors and also associated with angiogenesis and proliferation12. The relationship of the neo-angiogenic marker, endoglin with response to NACT has been reported13. Hence CD105 was also considered in the present study. Owing to the fact that the effects of steroid receptors are mediated through certain growth factors and their inhibitors are used as chemotherapeutic agents, studies are needed to evaluate the expression of steroid hormone receptors and growth factors, independently as well as in combination. This study was undertaken to assess the expression profile of AR in breast cancer cases and its interaction with other clinicopathological parameters, steroid receptors and growth factors to evaluate its clinical significance. Evaluation of the predictive ability of AR for the therapeutic response among LABC cases was also attempted.