We found varying amounts of ERalpha and ERbeta in normal ovaries, lower levels of ERbeta expression in ovarian epithelial cancer primary tumors, and only ERalpha in metastatic tumors. Our findings indicate that a fundamental difference might exist between primary and metastatic cells, which could be caused by intrinsic or extrinsic factors that regulate ER gene expression.

Mammary involution is associated with degeneration of the alveolar structure and programmed cell death of mammary epithelial cells. In this study, we evaluated the expression of Fas and Fas ligand (FasL) in the mammary gland tissue and their possible role in the induction of apoptosis of mammary cells. FasL-positive cells were observed in normal mammary epithelium from pregnant and lactating mice, but not in nonpregnant/virgin mouse mammary tissue. Fas expression was observed in epithelial and stromal cells in nonpregnant mice but was absent during pregnancy. At day 1 after weaning, high levels of both Fas and FasL proteins and caspase 3 were observed and coincided with the appearance of apoptotic cells in ducts and glands. During the same period, no apoptotic cells were found in the Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice. Increase in Fas and FasL protein was demonstrated in human (MCF10A) and mouse (HC-11) mammary epithelial cells after incubation in hormone-deprived media, before apoptosis was detected. These results suggest that the Fas-FasL interaction plays an important role in the normal remodeling of mammary tissue. Furthermore, this autocrine induction of apoptosis may prevent accumulation of cells with mutations and subsequent neoplastic development. Failure of the Fas/FasL signal could contribute to tumor development.J. Clin. Invest. 106:1209-1220.Terminal differentiation of the mammary gland normally takes place only during pregnancy and lactation when there is a cycle of lobulo-alveolar and ductal division followed by a period of lactation, after which cells of the secretory mammary epithelium and ducts become committed to apoptotic cell death. Gestational and lactogenic hormones regulate this pathway of differentiation. Changes in the hormonal environment at the end of lactation trigger the apoptotic signal required for "breast remodeling" (22, 23) perhaps also through the Fas-FasL system.To test the role of the Fas/FasL system in breast remodeling we studied the expression of Fas and FasL in the mammary tissue of normal BALB/c, MRL, C3H, as well as in Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice through the different stages of their lactogenic differentiation. We also evaluated the presence of apoptosis during involution in wild-type MRL and C3H mice and compared it with the natural knockout MRL/lpr and C3H/gld mice. To confirm our in vivo data we also studied caspase activation and apoptosis in normal human and mouse mammary epithelial cells. In this report we describe how Fas and FasL expression is altered during pregnancy, lactation, and postlactational period, and show how these changes are hormonally regulated. We also demonstrated the role of the Fas/FasL system as a mediator of apoptosis of mammary epithelial cells during the first stage of mammary gland involution. MethodsCells and culture condition. Cells were cultured in DMEM/F-12 media containing antibiotics and antimycotics (1% vol/vol) and proper serum at 37°C in a humidified chamber (5% CO 2 in air). C...

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Our findings support the hypothesis that the expression of FasL in normal ovary is hormonally sensitive and could have a key role in the physiology of normal ovarian tissue.