The Sex steroids, estradiol (E2) and progesterone, together with their cognate receptors, ER and PR are critical for normal mammary development and mammary carcinogenesis. A central role for PR in normal mammary development is established by the fact that in PR null mutant mice, which have ER, there is a severe inhibition in mammary growth. PR exits in two forms (the ~A~ and ~B~ forms) with varying activities. To identify the relative importance of the two isoforms and their role in normal mammary development and carcinogenesis, we created transgeneic mice carrying an imbalance in the native ration of f """"""""A"""""""" to """"""""B"""""""" forms by over expressing either the """"""""B"""""""" or """"""""B"""""""" form (referred to as PR-A and PR-B transgenics). The mammary development in both these strains of transgenics are abnormal and in PR-A transgenics, mammary glands exhibit dysplasias, suggesting increased propensity for tumorigenesis. The objective or this proposal is to identify the molecular mechanisms responsible for the altered growth patterns of mammary glands of PR-A and PR-B transgenics, assess their tumorigenic potential in vivo and determine if these arise from a perturbation in the cross-talk between ER, PR-A and PR-B.
The specific aims are: (1) To examine the mechanisms regulating cell proliferation and apoptosis in mammary glands of PR-A and PR-B transgenics and determine their relationships to expression and activities of ER, RP-A and PR-B. (2) To determine the tumorigenic potential of mammary glands of PR-A transgenics.
For specific aim 1, mammary glands from PR-transgenics exposed to E2 and progesterone in vivo will be (a) examined for changes in proliferation and apoptosis and their relationships to expression and activities of ER, PR-A and PR-B and (b) using cell culture and gene transfer techniques, the individual role of these receptors and their cross-talk in regulating proliferation and apoptosis will be dissected.
For specific aim 2, we will examine the growth behavior of PR-transgenic mammary glands upon serial transplantation and determine if upon exposure to a chemical carcinogen or by crossing with mice carrying a proto- oncogene, there is an acceleration in tumorigenesis. The uniqueness and major significance of the proposed studies is in our use of novel mouse models, for dissecting in physiological contexts, the individual roles of ER, PR-A and PR-B and their cross-talk in mediating normal mammary development and for assessing whether a derangement in these mechanisms, in itself, serves as a trigger for carcinogenesis, in particular, for the genesis of hormone dependent cancers.
Showing the most recent 10 out of 16 publications
