Progesterone Action in Human Breast Cancer

Institution: Lawrence Berkeley National Laboratory
Investigator(s): G. Shyamala Harris, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1IB-0448 Award: $85,733
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1995)
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 particular, both early menarche (beginning of menstruation) and late age onset of menopause have been shown to be associated with an increased breast cancer risk. Thus, it appears that it is the total length of time between menarche and menopause which is associated with the risk factor.

During each menstrual cycle, the ovaries synthesize and secrete the female sex steroids, estrogen and progesterone. Accordingly, the total length of time between menarche and menopause can be translated as the total years to which the normal breast is exposed to estrogen and progesterone. This, together with the fact that these ovarian steroids have been implicated in breast cancer for more than half a century, argues the need to target estrogen and progesterone as key factors responsible for the observed relationships between the reproductive history and breast cancer risk.

The normal breast is composed of several cell types and among these, it is the epithelial cells which are the ones most likely to give rise to cancers. In a normal breast, the epithelial cells divide during the progesterone dominant phase of the menstrual cycle, and these cells have a finite life span, such that there is a balance between this cell division and cell death. This balance is uncoupled in tumors accounting for their unrestricted growth. Therefore, by understanding how progesterone controls the division of epithelial cells in the normal breast, we can identify the potential steps which can become deranged and give rise to tumors.

The action of progesterone is controlled by progesterone receptors which are synthesized in response to estrogen. Therefore, to understand the role of estrogen and progesterone in breast cancer risk, it is particularly critical to understand the role of progesterone receptors on the normal breast. For this, we need to culture human breast epithelial cells containing progesterone receptors. At present, such a culture system does not exist. Although breast tumor cells containing progesterone receptors are available, the use of tumor cells (cells which have already undergone a derangement) is counterproductive for understanding the very basis for such derangement.

Thus, the goal of our proposal is to create normal human breast epithelial cell lines containing progesterone receptors and examine these for their responses to progesterone so that we may understand the role of progesterone in the breast cancer risk associated with the reproductive history of the female.


Final Report (1997)
The goal of our proposal was to create non-tumorigenic human breast epithelial cell lines containing progesterone receptors and examine them for their responses to progesterone so that we may understand the role of progesterone in the breast cancer risk associated with the reproductive female history. To achieve this, we screened a few well-characterized non-tumorigenic human mammary epithelial cell lines to determine if any of these contained progesterone receptors. At the same time, taking into consideration that most human breast cell lines do not contain progesterone receptors, we also modified the progesterone receptor gene to a form suitable for its introduction into various cell lines. Our attempts to introduce the progesterone receptor gene into the human mammary epithelial cell lines, so far, have met with failure. However, among the various cell lines examined, one contained significant levels of progesterone receptors that appeared to be functional as determined by the activation of a synthetic progesterone responsive element. Most importantly, it also appeared that as these cells began to acquire characteristics similar to that seen in tumorigenic cell lines, they began to lose progesterone receptors.

At present, to the best of our knowledge, this is the first time progesterone receptors have been identified in a non-tumorigenic human breast epithelial cell line. Although breast tumor cells containing progesterone receptors are available, the use of tumor cells (cells which have already undergone a derangement) is counter-productive for understanding the very basis for such derangement. In this regard, our cell culture model will be useful not only for studying the action of progesterone in non-tumorigenic human mammary epithelial cells but will also enable us to understand the relationship between the loss of progesterone receptors and hence, progesterone responsiveness and the acquisition of a tumorigenic phenotype. This, in turn, should allow us to better understand the role of progesterone in the breast cancer risk associated with the reproductive history of the female.