Progesterone Receptor and Remodeling of Basement Membrane

Institution: Lawrence Berkeley National Laboratory
Investigator(s): G. Shyamala Harris, Ph.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4JB-0142 Award: $120,681
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1998)
Epidemiological studies have clearly established that, excluding the genetic background, reproductive history is an important and consistent "natural" risk factor associated with breast cancer. In accordance with this, experimental models have clearly established that the female sex hormones, estrogen and progesterone, are essential for the development of both the normal breast and the induction of breast cancer. It is also well established that cancers most often arise from the undifferentiated (immature) structures present most frequently in the breast of females who have never given birth. The breast is composed of many cell types including the epithelial cells, which are the targets of normal growth and are the ones most likely to give rise to cancers. In a normal breast, the epithelial cells grow in response to progesterone, e.g. during the progesterone dominant phase of the menstrual cycle and pregnancy. More importantly, during pregnancy, the undifferentiated structures of the breast are converted to their differentiated (mature) counterparts. Using genetically engineered mice, our laboratory has direct proof that (a) this conversion of undifferentiated structures to differentiated structures requires progesterone and progesterone receptors, the protein through which progesterone action is mediated, and (b) when there is an alteration in the expression of progesterone receptors and progesterone responsiveness, there is abnormal development of mammary glands. Our recent studies also suggest that progesterone and progesterone receptors, in addition to regulating the growth and differentiation of epithelial cells, may also be involved in maintaining the integrity of the basement membrane present at the base of epithelial cells. Loss of basement membrane integrity can lead to migration of epithelial cells into adjacent tissue compartments and, in fact, contributes to the metastatic potential of tumors. Also, tumors with invasive properties are often hormone independent. Therefore, the goal of this project is to identify the potential involvement of progesterone and progesterone receptors in maintaining the integrity of the basement membrane and its link to progesterone and progesterone receptor mediated growth and differentiation of the breast. The results from these studies will provide crucial information with regard to whether a derangement in female sex steroid hormone action can trigger carcinogenesis due to inappropriate regulation and/or interactions with the basement membrane. Also, because of the potential utility of anti-progestins in the treatment of metastatic breast cancer, the results from these studies may also help in the selection of tumors most likely to respond to such treatments.


Progress Report 1 (1999)
The breast is composed of many cell types including the epithelial cells that are the targets for normal growth and are the ones most likely to give rise to cancers. In a normal breast, the epithelial cells grow in response to progesterone, for example during the progesterone dominant phase of the menstrual cycle and pregnancy. More importantly, it is during pregnancy that the undifferentiated (immature) structures of the breast are converted to their differentiated (mature) counterparts. It is well established that cancers most often arise from the undifferentiated structures present most frequently in the breast of young females that have never had babies. Using genetically engineered mice, our laboratory has found that (a) this conversion of undifferentiated structures to differentiated structures requires progesterone and progesterone receptors, the protein through which progesterone action is mediated, (b) when there is an alteration in the expression of progesterone receptors and progesterone responsiveness, there is abnormal development of mammary glands and (c) progesterone and progesterone receptors, in addition to regulating the growth and differentiation of epithelial cells, may also be involved in maintaining the integrity of the basement membrane present at the base of epithelial cells. Loss of basement membrane integrity can lead to migration of epithelial cells into adjacent tissue compartments and, in fact, contributes to the metastatic potential of tumors. Therefore, we are examining the potential involvement of progesterone and progesterone receptors in maintaining the integrity of the basement membrane and its link to progesterone and progesterone receptor mediated growth and differentiation of the breast. Our studies, so far, reveal that female sex steroids acting through their receptor can play a role in maintaining the integrity of the basement membrane and this can go wrong if there is an alteration in the action of these hormones. Therefore, our project will provide crucial information with regard to whether a derangement in female sex steroid hormone action can trigger carcinogenesis due to inappropriate regulation and/or interactions with the basement membrane. Also, because of the potential utility of anti-progestins in the treatment of metastatic breast cancer, the results from these studies may also help in the selection of tumors most likely to respond to such treatments.