Involvement of estrogen receptor β in terminal differentiation of mammary gland epithelium

Abstract

The mammary glands of prepubertal estrogen receptor (ER)␤؊͞؊ mice are morphologically indistinguishable from those of WT littermates. It appears that, although ER␤ is expressed in the mouse mammary gland, it is not involved in ductal growth of the gland. In this study, we examined the possibility that ER␤ has a role in the differentiated function of the mammary gland. Pregnancy is rare in ER␤؊͞؊ mice, but an intensive breeding program produced seven pregnant ER␤؊͞؊ mice, of which five did not eat their offspring and continued to successful lactation. Histomorphological comparison of lactating glands revealed that alveoli were larger and there was less secretory epithelium in ER␤؊͞؊ than in WT mice. Ultrastructural analysis showed abundant milk droplets and normal apical villi in the luminal epithelial cells, but the extracellular matrix and lamina basalis were reduced, and very frequently the interepithelial cell space was increased. Levels of the adhesion molecules, E-cadherin, connexin 32, occludin, and integrin ␣2 were reduced, and no zona occludens was detectable. In addition, there was widespread expression of the proliferation marker, Ki-67, in luminal epithelial cells in ER␤؊͞؊ but not in WT mice. These findings suggest a role for ER␤ in organization and adhesion of epithelial cells and hence for differentiated tissue morphology. We speculate that, because a reduced risk for breast cancer is conferred on women who breast-feed at an early age, ER␤ could contribute to this risk reduction by facilitating terminal differentiation of the mammary gland.lactation ͉ cadherin ͉ integrin ͉ tight junction T argeted disruption of estrogen receptor (ER)␤ in mice has revealed that this is a functional receptor in both males and females and that, in addition to its role in reproductive functions (1), it is also important in the cardiovascular (2) and central nervous systems (3). Female mice homozygous for the mutated ER␤ gene (ER␤Ϫ͞Ϫ mice) have been described as subfertile or infertile (4, 5). The ovarian defect is due to early atresia of antral follicles and failure to ovulate. As a result, corpora lutea are rare in ER␤Ϫ͞Ϫ mouse ovaries (6).Prepubertal ER␤Ϫ͞Ϫ females appear to have a normal mammary histology (5) with unaffected ductal outgrowth of the mammary gland anlage. However, because corpora lutea are rare, little progesterone is produced in the ovaries and, in contrast to their WT littermates, ER␤Ϫ͞Ϫ mammary glands fail to develop ductal side branches and alveoli after puberty. On administration of progesterone, side branching occurs, and mammary glands of ER␤Ϫ͞Ϫ mice appear morphologically indistinguishable from those of their WT littermates (7). As judged by nursing behavior and growth of their pups, ER␤Ϫ͞Ϫ mice have previously been reported to lactate effectively (5). In contrast, in female mice lacking aromatase (8) or ER␣ (9), mammary glands fail to develop beyond the prepubertal stage. From these studies, it has been concluded (5) that estrogen, acting through ER␣ but not through ER␤, is essential for norm...

Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β −/− mice

“…There is decreased expression of E-cadherin, connexin 32, occludin, and integrin ␣2 in mammary glands (15) and of ␣-catenin and plectin in the colon (18). These changes are accompanied by alterations in cytoarchitecture as revealed by EM (15,18,19).…”

“…Although ER␣ is the predominant ER in the adult rodent uterus, ER␤ mRNA has also been detected in WT and ER␣ Ϫ/Ϫ mouse uteri (11). Targeted disruption of ER␤ in mice (12) has revealed roles for ER␤ in differentiation of various epithelial and nonepithelial cell types in many tissues and organs (13)(14)(15)(16)(17)(18)(19). In the uteri of ER␤ Ϫ/Ϫ mice, there is an exaggerated responsiveness to E 2 , resulting in enlargement of the lumen, increase in volume and protein content of uterine secretion, and induction of aberrant epithelial expression of PR after E 2 injection (13).…”

ERβ in breast cancer—Onlooker, passive player, or active protector?

“…In support of this, abnormal epithelial growth, expression of the proliferation marker Ki67, and age-related cystic breast disease were observed in one model of BERKO mice [57,69]. However, these results have not been replicated in other BERKO mouse models, and normal mammary gland histology was observed in a recently developed model of old BERKO females [41].…”

“…In BERKO mice, this development is not impaired, nor is lactation [19]. However, one group has observed decreased terminal differentiation, adhesion molecule expression, and increased proliferation marker expression in the alveoli of lactating BERKO mice [57].…”

Estrogen receptor α and β in uterine fibroids: a basis for altered estrogen responsiveness

“…In fact, it has been reported that ERa and ERb have opposite effects on AP1 sites and that they probably have different roles as regards regulation of AP1-dependent genes, including genes involved in the control of cell growth and viability (12). In the mammary gland, ERa and ERb are pivotal for tissue development and terminal differentiation, respectively (13,14). In line with this, 17b-E 2 (hereafter referred to as E 2 ) has been reported to promote the growth of immortalized mammary cells through ERa and inhibit it through ERb (15).…”