Fate Mapping of Progesterone Receptor Positive Breast Cells

Institution: Lawrence Berkeley National Laboratory
Investigator(s): G. Shyamala Harris, Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3IB-0034 Award: $243,380
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1997)
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 steroids, estrogen and progesterone, are essential for both the development of the normal breast and the induction of breast cancer. It is also well established that cancers most often arise from the undifferentiated structures present most frequently in the breast of young females who have never been pregnant.

The breast is composed of many cell types including the epithelial cells, which 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 e.g. during the progesterone dominant phase of the menstrual cycle and pregnancy. More importantly, it is during pregnancy that the undifferentiated structures of the breast are converted to their differentiated counterparts. Using genetically engineered mice, our laboratory has direct proof that this conversion of undifferentiated structures to differentiated structures requires progesterone and progesterone receptors, the protein through which progesterone action is mediated. We have also found that epithelial cells that contain the progesterone receptor are a distinct subset. Thus, we believe that the loss of progesterone receptor positive cells, or a loss in the ability of progesterone receptor to convert undifferentiated cells to a differentiated state, increases the sub-population of cells at risk for breast cancer. Our long-term objective, therefore, is to follow the fate of progesterone receptor positive cells as they undergo normal development during pregnancy and when they are exposed to cancer risk. For this, we need to create animal experimental models in which we can follow the fate of epithelial cells containing progesterone receptor and their negative counterparts on a cell by cell basis in a heritable manner. At present, such a system does not exist. Therefore, the goal of our project is to create genetically engineered mice that can be used to meet the long-term objectives of this grant.


Final Report (1999)
The long term objective of our proposal was to follow the fate of progesterone receptor positive cells in normal breast as they undergo development during pregnancy and when they are exposed to cancer risk. Progesterone receptor is a protein through which the action of the female sex steroid, progesterone, is mediated. To achieve our goal, we had proposed to create three separate types of genetically engineered mice. Studies on one of these transgenic mice have revealed a very significant phenomenon pertaining to normal breast development - that a part of the progesterone receptor gene may contain information capable of impeding breast development. In particular, this growth impairment affects parts of the mammary ducts that represent the undifferentiated (immature) structures. It is well established that cancers most often arise from the undifferentiated structures in the breast. Therefore, these transgenic mice created by our laboratory can serve as an important experimental model to obtain critical insights regarding the mechanisms by which the undifferentiated structures of the breasts arise. When we achieve these goals, we can apply our findings directly to alter the behavior of cancer cells. Our findings can also be used for designing prophylactic strategies.