Date of Award

2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Animal Nutrition and Food Science

First Advisor

Zhongzong Pan

Second Advisor

Andre-Denis Wright

Abstract

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 α (ERα) and estrogen receptor β (ERβ). Both ERα and ERβ are expressed in the mammary gland, but with distinct expression patterns. In the mammary gland, ERα has been proved to be the estrogen receptor that mediates the mitogenic function of estrogen. However the function of ERβ in mammary cell proliferation is less understood and there remains some controversy. Accumulating evidence indicates that ERβ, unlike ERα, is a negative regulator of mammary epithelial cell proliferation.

In this dissertation, ERα and ERβ were evaluated for their expression patterns in the mammary gland. In the proestrus phase, ERα was detected in about 20% of mammary epithelial cells; in the diestrus phase, no ERα staining was detected in the mammary gland. ERβ was expressed in more than 50% of mammary epithelial cells and ERβ staining was detected in some stromal cells in the proestrus phase. In the diestrus phase, ERβ staining cells were very limited and the staining intensity was very weak. These data suggest that the expression levels of both ERα and ERβ undergo dynamic changes during the estrous cycle. In the ovariectomised (OVX) rats, both ERα and ERβ 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 ERα expression, but the staining intensity was weaker. Taken together, the expression of ERα and ERβ is regulated by estrogen in normal mammary gland, while without estrogen stimulation in the OVX rats, more mammary cells showed ERα expression, but at a lower level in these cells.

The effects of ERα and ERβ on mammary cell proliferation were studied by two different approaches, activation of endogenous ERα and ERβ via selective agonists, and overexpression of ERα and ERβ via lentiviral infection. In the first approach, we used ERα and ERβ selective agonists, propylpyrazole-triol (PPT) and diarylpropionitrile (DPN) respectively, to activate endogenous ERα and ERβ in the OVX rats. We found that ERβ selective agonist DPN counteracts the proliferative effect of ERα selective agonist PPT in the mammary gland. In the second approach, ERα and ERβ were ectopically overexpressed in the mammary gland of mature virgin rats by lentivirus infection. We found that ERβ overexpression significantly decreased mammary cell proliferation rate in both the proestrus and diestrus phases, indicating that ERβ, unlike ERα, is a negative regulator for mammary cell proliferation. Collectively, these data supports that in contrast to ERα, ERβ activation or overexpression is able to inhibit mammary cell proliferation.

Language

en

Number of Pages

251 p.