Prolactin (PRL) and prolactin receptor (PRLR) are members of cytokine super family. Overproduction of PRL by prostate cells results in prostatic hyperplasia in mice. Elevated serum PRL levels induced by estrogens, positive regulators of PRL, or by drugs result in rodent prostatic hyperplasia and enhanced rodent prostatic tumor growth. In rodents, hyperprolactinemia and prostatic hyperplasia are also induced by bisphenol A (BPA), an environmental estrogen. Together, this provides evidence that PRL plays a critical role in rodent prostatic hyperplasia and carcinogenesis. However, our knowledge on the role of PRL in human prostatic growth is limited and the mitogenic potential of PRL in the progression of human prostate cancer remains unexplored. Our preliminary data document expression of PRL and PRLR in different prostate cancer cells, up-regulation of PRLR expression by PRL, and increased cell proliferation in response to PRL. In addition, we show a rapid phosphorylation of ERK1/2 in response to PRL, estradiol (E2) as well as BPA. Accordingly, our hypothesis is """"""""Human prostate cancer cells produce PRL and form a functional autocrine-paracrine regulatory loop of PRL and the PRLR. The autocrine-paracrine effects of PRL/PRLR as well as the combined actions of PRL and estrogens contribute to the progression of prostate cancer. Both PRL and estrogens recruit components of the MAP kinase signaling cascade."""""""" To test our hypothesis we will use DU 145 human prostate cancer cells as a model. The following specific aims will investigate the direct as well as combined effects of PRL, E2 and BPA.
Specific Aim 1 : To determine: a) local production of biologically-active PRL and its effects on cell proliferation; b) the effects of exogenous PRL, E2 and BPA on PRLR and estrogen receptor (ER)-beta expression; c) the effects of exogenous PRL, E2, and BPA on cell proliferation; d) the binding parameters of PRLR in the cells; e) the ability of tamoxifen to inhibit PRL effects via PRLR.
Specific Aim 2 : To examine: a) PRL induced activation of STATs and their nuclear translocation; b) activation of ERK1/2 by various treatments and their nuclear translocation; c) the enzymatic activities of Raf, MEK and MAP kinases; d) the role of the MAP kinase cascade in mediating the mitogenic responses to PRL, E2, and BPA. The results of this study should provide information on the role of local PRL and the combined actions of PRL and estrogens on prostate cancer cell proliferation. The findings on BPA may reveal the potential risk associated with human exposure to environmental estrogens.
| Kansra, Sanjay; Yamagata, Sayaka; Sneade, Leighton et al. (2005) Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol 239:27-36 |
| Liby, Karen; Neltner, Bonnie; Mohamet, Lisa et al. (2003) Endostatin expression by MDA-MB-435 breast cancer cells effectively inhibits tumor growth. Cancer Biol Ther 2:48-52 |
