ProgesteronePR Signaling in Mammary Carcinogenesis

Most of the classical studies on the developmental biology of the normal mammary gland and mammary oncogenesis have been done in rodents. Conclusions derived from these studies have been found to be applicable to the human condition (19). Furthermore, the pattern of PR localization in normal mouse mammary glands is

similar to that reported previously for human breast, i.e., (a) PR expression in the epithelial cells is heterogeneous, and (b) the connective tissue surrounding these epithelial cells are PR free (7, 20).

In normal mammary epithelial cells, the initial impact of progesterone signaling through PR results in an increase in proliferation. Therefore, in its capacity as a mammary gland mitogen, progesterone has the potential to trigger carcinogenesis. An excellent example of this P action is the animal model developed by Lanari et al. in which the progestin, medroxyprogesterone induces mammary tumors (21). Another example is the p53-null mutant mammary epithelium in which progesterone alone strongly enhances mammary tumorigenesis (22). Studies from our laboratory (as reviewed here) showed that a deregulation in progesterone action (as in PR-A transgenics) can alter the growth potential of epithelial cells, at least, in part, at the level of cell cycle, leading to transformation. Recent population based studies also demonstrated that, in uninterrupted combined hormone (estrogen + progestin) replacement therapy (CHRT), progesterone is the contributing factor for the increased risk for mammary carcinogenesis (23). Also, studies on normal mammary development established that the net outcome of signaling through PR is to drive the epithelial cells towards lobulo-alveolar development. Thus, it is noteworthy that women who are at increased risk for mammary oncogenesis due to CHRT develop lobular carcinomas (24).

Studies from our laboratory clearly established that an imbalance in the expression of the two PR isoforms, resulting from PR-A overexpression, may lead to transformation of mammary epithelial cells. An imbalance in the relative ratio of PR A:B isoforms has also been observed in certain human mammary tumors, and has often been associated with overexpression of the PR-A form (25-27).

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