Control of the Mammary Cell Cycle Clock by Estrogen and Progesterone
Abstract
Both the growth and the development of the mammary gland are controlled by the female hormones estrogen, prolactin and progesterone, and by interactions between the epithelial and stromal compartments of the breast. Changes in the regulation of any of these processes may lead to breast cancer. We have investigated the role of progesterone in the process of sidebranching and alveologenesis in the mammary gland using mice lacking the progesterone receptor which are defective in these processes. By reconstituting murine mammary glands in vivo, we have shown that the progesterone receptor is required only in epithelial cells for proper sidebranching and alveologenesis to occur. Our studies indicate that progesterone acts in a paracrine manner and suggest that Wnt-4 is a mediator of the paracrine signals released from progesterone receptor-positive cells. In addition, we have characterized the role of the estrogen receptor (ER) in regulating the proliferation of breast cancer cells. We postulate that the ability of ER to control cyclin Dl expression and proliferation of breast cancer cells may be acquired during breast cancer progression. This is indicated by the fact that ectopic expression of the estrogen receptor in human epithelial cells does not, on its own, enable signaling between the ER and the cyclin D1 gene. Moreover, others have demonstrated that the ER-positive cells in the mammary epithelium are distinguishable from those that are actively mitotic. Finally, our work indicates that the effects of deletion of the prolactin receptor (PrlR) from mammary epithelial cells closely phenocopy the consequences of deleting cyclin Dl from these cells. We suggest that activation of the PrlR by its ligand results in the production of insulin-like growth factor-2 which in turn induces cyclin D1 synthesis in these cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2001
- Accession Number
- ADA391253
Entities
People
- Robert Weinberg
Organizations
- Whitehead Institute