Role of Progesterone in the Etiology of Breast Cancer

Our studies reveal that with increasing age mammary glands acquire a greater sensitivity to estrogen and progesterone which becomes very evident at -8 months of age. The increased sensitivity to estrogen and progesterone is reflected both at the morphological level and in the expression of progesterone receptor. In transgenic mice carrying an imbalance in the native ratio of the two isoforms of progesterone receptor, mammary glands exhibit an altered sensitivity to estrogen and progesterone which is evident at both morphological level and in the pattern of cell proliferation. At the level of progesterone receptor expression, interestingly, the glands of young transgenic mice and -8 month old mice somewhat resemble each other. These observations indicate that estrogen and progesterone and the two isoforms of progesterone receptor may be the key factors responsible for maintaining the mammary glands of adult females in a quiescent state and a derangement in these mechanisms can trigger inappropriate cell proliferation and hence, carcinogenesis. As such, they provide evidence to the stated hypothesis of this proposal, i.e. there is a need to target estrogen and progesterone and progesterone receptors as critical factors responsible for the observed relationships between the reproductive history and breast cancer risk.