摘要：

Excluding cancers of the skin, breast cancer is the most common cancer among women, accounting for nearly one of every three cancers diagnosed in American women. Among the endocrine factors associated with breast cancer, estrogens, such as estradiol-17[beta] (E2), are considered to play a central role in human breast carcinogenesis. Zeranol (Z) (Ralgro), a nonsteroidal agent with estrogenic activities, is used as a growth promoter in the U.S. beef, veal and lamb industries. We showed E2 and Z induced human breast epithelial cell neoplastic transformation with the similar potency in the long-term exposure through the redox-pathway and/or ER[beta] pathway and they have the similar potency in regulating some target gene expressions in human breast cancer cells. Protein tyrosine phosphatase y (PTPy), a member of the receptor-like tyrosine-specific phosphatase family, has been implicated as a tumor suppressor gene in kidney and lung cancers. In our study, we found that PTPy was mainly immunolocalized to the epithelium and PTPy mRNA expression was lower in cancerous than in normal breast tissues, and both E2 and Z downregulated PTPy expression when estrogen receptor a (ERa) was present in human breast and that epithelial-stromal cell interaction was important in the regulation of PTPy expression by estrogenically active agents. Based on these findings, we hypothesized that PTPy might be involved in neoplastic processes of human breast epithelium, which led us to examine the action of PTPy on in vitro growth of human breast cancer cell line MCF-7. Our results showed that PTP[gamma]a overexpression inhibited the MCF-7 cell proliferation and led to a decrease in the anchorage-independent growth of MCF-7 cells in soft agar. Our data suggested that PTPy might function as a potential tumor suppressor gene in regulating human breast tumorigenesis. Collectively, these studies provide new insight into the role of Zeranol in human breast neoplastic transformation and the importance of PTPy in the suppression of human breast carcinomas, and shed a light on the tight relationship among estrogen, PTPy and breast cancer. The investigations provide rationales for the development of therapeutic approaches targeting on PTPy as a breast cancer suppressor. Title from first page of PDF file. Document formatted into pages; contains xviii, 158 p. : ill. (some col.). Thesis (Ph. D.)--Ohio State University, 2003. Includes bibliographical references (p. 148-158). Advisor: Young C. Lin, Veterinary Biosciences Graduate Program.

展开