Hormone prevention of mammary carcinogenesis: a new approach in anticancer research

The observation that chemically induced breast cancer is prevented when the mammary gland is completely differentiated by a full term pregnancy prior to exposure to a carcinogen, led us to test the hypothesis that synthetic ovarian hormones commonly used for the purpose of contraception might drive mammary gland differentiation enough to be protective from carcinogen--induced neoplastic transformation. This hypothesis was only partially proven, due to the unexpected finding that a high dose of the progestagenic agent medroxyprogesterone acetate (MPA), increased tumor incidence, whereas a similar dose of the mostly estrogenic norethynodrel--mestranol (NM) was protective. An additional finding was the fact that these two agents exerted a different action on thoracic than on abdominal mammary glands. MPA inhibited differentiation of TEBs in the former, but stimulated lobule development in the latter. This difference in response seemed to be associated to the asynchronous development of the mammary glands located in different topographic regions. These observations indicated that the response of the mammary gland epithelium with either differentiation or cell proliferation is in great part modulated by the condition of the target organ. Although the concept of hormone prevention of breast cancer promises to be an achievable goal, there are still basic fundamental questions that need to be answered. First, how do estrogens and progesterone act on the mammary epithelium, second, what is the sequence in which they act on the mammary gland in order to induce differentiation of the organ, third, why the same homonal milieu in a single animal results in asynchronous development of glands located in thoracic versus those in the abdominal region.