A ctivins and inhibins are members of the transforming growth factor-B (TGF-I) superfamily, which consists of TGF-I), activins, bone morphogenic proteins (BMPs), anti-Mullerian hormone (AMH), and others. These structurally related growth factors have essential functions in regulating tissue development, homeostasis, cell proliferation, and apoptosis. Activin and inhibin were originally isolated based on their activity in regulating follicle-stimulating hormone (FSH) release from the anterior pituitary: activin stimulates, whereas inhibin inhibits FSH secretion (1, 2). In addition to its endocrine function, activin has been found to possess various activities in different biological systems, e.g., erythroid differentiation, nerve cell survival, Xenopus laevis embryonic mesoderm induction, bone growth promotion, and somatostatin induction (3, 4). Subsequently, it was found that activin regulates a wide variety of cellular events, including cell proliferation, differentiation, and apoptosis. For example, in addition to its endocrine function in the pituitary, activin also controls the activity of hypothalamus and ovary (reviewed in Ref. 5), indicating that activin has profound paracrine and autocrine effects on the female reproductive system. In addition, activin expression has been detected in cell lines derived from various human tissues, including prostate cancer (6-8), breast cancer (9, 10), retinoblastoma (11), retinal pigment epithelium (12) placenta (13), gut (14), and bone marrow stroma (15), as well as a number of in vivo human tissues, including the testis (16), ovary (17), endometrium (18), placenta (19), oocyte (20), adrenal CELL PROLIFERATION, APOPTOSIS, AND CARCINOGENESIS 75 Research in the laboratories of Dr. Shao-Yao Ying was supported by the National Institutes of Health (grants HD 22876. HD24648. OK 47607. and CA 85772). Research in the laboratory of Dr. Ye-Guang Chen was supported by the Bugher Foundation. by the University of California Cancer Research Coordinating Committee. and by UCR Start-Up Funds. I This manuscript is an update of a previously published minireview (Proc Soc Exp Bioi Med 214: 114-122. (997).

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The importance of epidermal growth factor (EGF) in both normal and malignant mammary gland development are presented in these studies. Initial findings demonstrated that in the absence of ovarian hormones, EGF had a significant proliferative effect on mammary epithelial cells. To determine whether mammary epithelial cells grown with EGF, in the absence of ovarian hormones, could be transformed by N-methyl-N-nitrosourea (MNU), female ovariectomized Lewis rats were implanted with pellets containing EGF for 1 week and then treated with MNU for initiation. Two days after MNU treatment, ovaries were implanted and EGF pellets were removed from all ovariectomized groups in order to promote carcinogenesis. The mammary carcinoma incidence of the EGF-stimulated group (90%) was not significantly different from the intact group (100%). The mammary cancer morphology of EGF-treated carcinomas was either ductal carcinoma or cribriform adenocarcinoma, whereas intact animals developed mainly papillary and occasional cribriform carcinomas. Fifty-eight percent of the carcinomas from the EGF group were ovarian hormone-independent compared with 10% of carcinomas from the intact group. These results demonstrate that EGF-induced proliferation during initiation with MNU was sufficient to induce the transformation of mammary carcinomas in the absence of ovarian hormones. The hormonal dependency of these EGF-induced carcinomas were different compared with MNU-initiated mammary carcinomas in intact rats.

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