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

Breast cancer is the most common cancer and the second most frequent cause of cancer death in women. Despite extensive research, the precise mechanism s of breast carcinogenesis remain unclear. We have shown that in female rat s, treatment with a combination of oestrogen and testosterone can induce a high incidence of mammary cancer. The dosage of testosterone affects only t he latency period of mammary cancer, not the final incidence. Based on thes e observations, we hypothesize that oestrogen and androgens may act in conc ert on the mammary gland to induce mammary carcinogenesis, with oestrogen s erving as the predominant initiator whereas the androgen acts as a major pr omoter. In the present study, we report the changes in morphology of the ma mmary gland with special emphasis on the perialveolar or interlobular strom a after treatment with various sex hormone protocols, Our data showed that after treatment with testosterone, either alone or in combination with 17 b eta-oestradiol, there was overexpression of the androgen receptor in alveol ar or ductal epithelial cells, Concurrent with strong expression of the and rogen receptor in epithelium, there was also an increase in the amount of p erialveolar and interlobular connective tissue, a decrease in surrounding a dipose tissue and an increase in proliferation rate of fibroblast-like cell s in the stroma, All these changes were blocked by simultaneous implantatio n of flutamide, indicating that androgens play a crucial role in the proces s despite the absence of androgen receptors in stromal cells. We further me asured the mammary gland density (MGD), in order to determine the ratio of fatty to non-fatty tissue, The data showed that MGD values were significant ly higher in animals treated with testosterone alone or in combination with 17 beta-oestradiol than in those treated with 17 beta-oestradiol alone or in controls. Furthermore, treatment with different doses of testosterone re sulted in an increase in MGD in a dose-dependent manner. These findings hig hlight the effect of androgens on the stroma, probably through a paracrine action of epithelial cells. The stroma may, in turn, promote mammary carcin ogenesis in a reciprocal fashion.