| The mammary gland cell growth and differentiation are under the control of both systemic hormones and locally produced growth factors. Among all these important hormones and growth factors, estrogen plays a central role in mammary gland development. The biological function of estrogen is mediated by estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). Both ERalpha and ERbeta are expressed in the mammary gland, but with distinct expression patterns. In the mammary gland, ERalpha has been proved to be the estrogen receptor that mediates the mitogenic function of estrogen. However the function of ERbeta in mammary cell proliferation is less understood and there remains some controversy. Accumulating evidence indicates that ERbeta, unlike ERalpha, is a negative regulator of mammary epithelial cell proliferation.;In this dissertation, ERalpha and ERbeta were evaluated for their expression patterns in the mammary gland. In the proestrus phase, ERalpha was detected in about 20% of mammary epithelial cells; in the diestrus phase, no ERalpha staining was detected in the mammary gland. ERbeta was expressed in more than 50% of mammary epithelial cells and ERbeta staining was detected in some stromal cells in the proestrus phase. In the diestrus phase, ERbeta staining cells were very limited and the staining intensity was very weak. These data suggest that the expression levels of both ERalpha and ERbeta undergo dynamic changes during the estrous cycle. In the ovariectomised (OVX) rats, both ERalpha and ERbeta were detected in more than 50% of mammary epithelial cells. Compared with the ovary-intact rats, the mammary gland of the OVX rats showed more cells with ERalpha expression, but the staining intensity was weaker. Taken together, the expression of ERalpha and ERbeta is regulated by estrogen in normal mammary gland, while without estrogen stimulation in the OVX rats, more mammary cells showed ERalpha expression, but at a lower level in these cells.;The effects of ERalpha and ERbeta on mammary cell proliferation were studied by two different approaches, activation of endogenous ERalpha and ERbeta via selective agonists, and overexpression of ERalpha and ERbeta via lentiviral infection. In the first approach, we used ERalpha and ERbeta selective agonists, propylpyrazole-triol (PPT) and diarylpropionitrile (DPN) respectively, to activate endogenous ERalpha and ERbeta in the OVX rats. We found that ERbeta selective agonist DPN counteracts the proliferative effect of ERalpha selective agonist PPT in the mammary gland. In the second approach, ERalpha and ERbeta were ectopically overexpressed in the mammary gland of mature virgin rats by lentivirus infection. We found that ERbeta overexpression significantly decreased mammary cell proliferation rate in both the proestrus and diestrus phases, indicating that ERbeta, unlike ERalpha, is a negative regulator for mammary cell proliferation. Collectively, these data supports that in contrast to ERalpha, ERbeta activation or overexpression is able to inhibit mammary cell proliferation. |
