The mammary gland is a complex organ whose growth and development are controlled by the interaction of a wide variety of hormones and growth factors. These same factors play fundamental roles in the etiology and progression of the cancerous state. The first event in the action of these hormones and growth factors is the interaction with specific cell associated receptors. The availability and activity of each class of receptor is regulated by the ligand which it recognizes as well as the general hormonal/growth factor milieu of the target cell. Our emphasis has been on the interactions of prolactin (Prl), estrogens, and progesterone, with recent work also examining how epidermal growth factor (EGF), and transforming growth factors alpha and beta are affected by the interplay of these three classical hormones. Lobulo- alveolar development of the mammary gland requires the priming action of both estrogen and progesterone to induce EGF receptors and production of EGF-like growth factors. In concert with insulin, Prl and glucocorticoids, EGF or TGF-alpha can promote full lobulo-alveolar development in vitro. High concentrations of the somatogenic hormone, growth hormone, can substitute for Prl in this system. This effect is not mediated through insulin-like growth factor I. Programmed cell death occurs within 3 days of removal of Prl. This apoptosis is accompanied by an increase in expression of TGF-beta1 and TGF-beta3. Prl induced growth of the mouse mammary epithelial cell, NOG-8, involves activation and translocation of protein kinase C (PKC). In addition, raf-1, MEK and MAP kinases are activated withian 1 to 5 min. by Prl in NOG-8 and T47D cells. When NOG-8 cells are transformed with ras oncogene they lose the ability to bind Prl when grown in the presence of charcoal stripped serum. This effect is reversed by the addition of Prl to the culture medium, or by introducing the rsp-1 ras suppressor gene. Finally, we have explored the relationship of a membrane associated antilactogen binding site (ALBS) to the Prl receptor on human breast cancer cell growth in culture. Prl induced growth of human breast cancer cells can be blocked by non-steroidal antiestrogens such as tamoxifen. This action is through the ALBS which appears to be intimately associated with the Prl receptor. These studies are greatly aided by use of monoclonal antibody B6.2 which is the first known such antibody to recognize the human Prl receptor. The antiprolactin action of tamoxifen, working through the ALBS, may have important clinical implications.
