Roles of Fas and Fas ligand during mammary gland remodeling

Abstract

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...

Hsp70 may protect cardiomyocytes from stress-induced injury by inhibiting Fas-mediated apoptosis

“…The evidence presented above indicates that overexpression of Hsp70 could mitigate stress-induced cardiomyocyte injury and exert its cytoprotective action on the heart. The Fas pathway is an important pathway of apoptosis that controls cell proliferation and tissue remodeling (Song et al 2000). Triggering of Fas by either agonistic antibodies or FasL results in receptor oligomerization and recruitment of the adaptor protein, Fas-associated death domain (FADD), which along with procaspase-8, forms a death-inducing signaling complex (DISC) (Kischkel et al 1995).…”

Maternal serum of women with pre-eclampsia reduces trophoblast cell viability: evidence for an increased sensitivity to Fas-mediated apoptosis

“…The Fas/FasL system is expressed in immune as well as non-immune cells, such as trophoblasts [19][20][21][22]31 . Its expression and function respond to changes in the microenvironment, and play a pivotal role in controlling cell proliferation and tissue remodeling 22,[32][33][34][35] . Both FasL and Fas are transmembranous proteins of the tumor necrosis factor (TNF)-a/TNF-a-receptor family.…”

Impaired lactation in mice expressing dominant‐negative FADD in mammary epithelium

“…1c), together with the defect noted during lactation. However, it is likely that FADD also has distinct roles during mammary gland involution (Song et al, 2000;Clarkson et al, 2004).…”

“…Examination of Fas-deficient (MRL/lpr) and FasL-deficient (C3H/gld) mice suggested a role for death receptor signaling in the initial phase of mammary gland involution, which is normally characterized by coordinated, wide-scale apoptosis (Song et al, 2000). In support of this, mRNA expression of death receptor family members, including FADD, is up-regulated during the initial phase of involution (Clarkson et al, 2004).…”