Sex hormone-induced mammary carcinogenesis in female Noble rats: The role of androgens

Abstract

Breast cancer is the most common cancer and the second most frequent cause of cancer death in women. Despite extensive research, the precise mechanisms of breast carcinogenesis remain unclear. We have shown that in female rats, treatment with a combination of oestrogen and testosterone can induce a high incidence of mammary cancer. The dosage of testosterone affects only the latency period of mammary cancer, not the final incidence. Based on these observations, we hypothesize that oestrogen and androgens may act in concert on the mammary gland to induce mammary carcinogenesis, with oestrogen serving as the predominant initiator whereas the androgen acts as a major promoter. In the present study, we report the changes in morphology of the mammary gland with special emphasis on the perialveolar or interlobular stroma after treatment with various sex hormone protocols. Our data showed that after treatment with testosterone, either alone or in combination with 17β-oestradiol, there was overexpression of the androgen receptor in alveolar or ductal epithelial cells. Concurrent with strong expression of the androgen receptor in epithelium, there was also an increase in the amount of perialveolar and interlobular connective tissue, a decrease in surrounding adipose tissue and an increase in proliferation rate of fibroblast-like cells in the stroma. All these changes were blocked by simultaneous implantation of flutamide, indicating that androgens play a crucial role in the process despite the absence of androgen receptors in stromal cells. We further measured the mammary gland density (MGD), in order to determine the ratio of fatty to non-fatty tissue. The data showed that MGD values were significantly higher in animals treated with testosterone alone or in combination with 17β-oestradiol than in those treated with 17β-oestradiol alone or in controls. Furthermore, treatment with different doses of testosterone resulted in an increase in MGD in a dose-dependent manner. These findings highlight the effect of androgens on the stroma, probably through a paracrine action of epithelial cells. The stroma may, in turn, promote mammary carcinogenesis in a reciprocal fashion.