Both endogenous and exogenous
estrogen exposure is associated with an increased
breast cancer risk. In some studies, elevated serum
testosterone levels have also been linked to an increased
breast cancer risk.
Estrogen alone or combined with
progesterone induces high mammary
tumor incidences in various strains of both male and female rats. Mammary gland ductal
adenocarcinomas were induced after 17beta-estradiol (E2) and
testosterone propionate (TP) treatment in male Noble rats.
Tumor incidence was 100% after 8-9 months of treatment. Such
neoplasms were not detected after either
estrogen or
androgen exposure alone within this time period. TP alone caused disruption of mammary gland ducts and proliferation of stromal tissue, while E2 treatment alone induced both ductal epithelial growth and nodular atypical
hyperplasia. To study the interaction of these
hormones in mammary
tumorigenesis,
sex hormone receptors were characterized in mammary glands of Noble rats.
Estrogen receptor-alpha (ER) was detected in age-matched, untreated mammary gland epithelium; in most early atypical hyperplastic lesions appearing after E2 and E2 + TP treatment and in E2 + TP-induced mammary
tumors. Two major ER putative
isoforms, 116 and 120 kDa, were detected in E2- and E2 + TP-treated mammary glands, and in the induced
tumors. A 54 kDa ER
protein was found in untreated and TP-treated mammary glands, and in the induced
tumors. Both
progesterone receptor-B (PR-B) and PR-A2, as well as
androgen receptor-B (AR-B) and AR-A
isoforms were markedly elevated in all E2 + TP-induced mammary
tumors. However, the levels of both PR and AR were very low in mammary glands of E2- and E2 + TP-treated male rats. Low and moderate levels of AR and PR, respectively, were detected in most atypical hyperplastic lesions induced by E2- and E2 + TP-treated mammary glands. These results suggest that
androgens may interact with either AR or PR, and perhaps both receptors, in E2 + TP-induced mammary glands and the induced
tumors to effect the reduction in latency period, enhance
tumor size, and increase incidence to 100%.