Estrogenic and Antiestrogenic Regulation of Cell Proliferation and Tissue Growth

133 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1987.Estrogenic and antiestrogenic responses were investigated in human breast cancer cells and in the rat uterus. I studied the regulation of ornithine decarboxylase (ODC) activity and polyamine concentrations by E2 and antiestrogens (AE) as an aid to understanding the dissimilar effects of E2 and AE on uterine growth. Both E2 and AE stimulated ODC activity. AE were antagonistic to E2 in that pretreatment with either CI628 or U23,469 prevented the second estradiol stimulated peak in ODC activity. Polyamine concentrations on a per cell basis were similarily elevated in E2 or AE treated uteri. The degree to which the uterus is stimulated to grow in response to E2 and/or AE appears to be paralleled closely in the magnitude of its ODC activity and in its total accumulated levels of polyamines per uterus.The importance of the polyamine biosynthetic pathway in hormonal regulation of cell proliferation and progesterone receptor levels was determined in the MCF-7 cell line. Use of difluoromethylornithine (DFMO), an irreversible inhibitor of ODC activity, indicated that the integrity of the polyamine biosynthetic pathway was essential for estrogenic regulation of cell proliferation. Yet, the antiproliferative effects of antiestrogens were not due to depletion of intracellular polyamine levels. Not all estrogenic responses are dependent on an intact polyamine biosynthetic pathway, in the DFMO had no effect on estrogenic regulation of progesterone receptor levels.I investigated the effects of AE on the proliferation of MCF-7 cells grown in the absence of phenol red, a weak estrogen. Upon immediate removal of phenol red from the media, the cell proliferation rate was reduced. The AE, tamoxifen, then acted as a partial E agonist and antagonist in terms of both cell proliferation and cell cycle kinetics. When MCF-7 cells were maintained in the absence of phenol red for six months, the cells adapted. Their control growth rate increased and AE became inhibitory to control cell proliferation. After adaptation E2 was able to reverse the antiproliferative effects of AE, yet E2 was unable to stimulate cell proliferation. This altered hormonal responsiveness was not due to changes in estrogen receptor levels.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD