Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during Growth, Differentiation, and Apoptosis of Normal Rat Mammary Epithelial Cells

Abstract

Studies were undertaken to examine the natural role of ErbB2, ErbB3, and ErbB4 during the development of normal rat mammary epithelial cells (MECs) in vivo and in vitro. Immunohistochemical analysis demonstrated that mammary gland terminal end buds expressed abundant ErbB2 and ErbB4 but limited ErbB3 in pubescent rats, whereas luminal epithelial cells in nulliparous rats expressed ErbB2, ErbB3, and/or ErbB4. During pregnancy, ductal epithelial cells and stromal cells expressed abundant ErbB3 but limited ErbB2. Although ErbB2 and ErbB3 were downregulated throughout lactation, both receptors were re-expressed during involution. In contrast, ErbB4 was downregulated throughout pregnancy, lactation, and involution. Immunoblotting and immunoprecipitation studies confirmed the developmental expression of ErbB2 and ErbB3 in the mammary gland and the co-localization of distinct ErbB receptors in the mammary gland of nulliparous rats. In agreement with our in vivo findings, primary culture studies demonstrated that ErbB2 and ErbB3 were expressed in functionally immature, terminally differentiated and apoptotic MECs, and downregulated in functionally differentiated MECs. ErbB receptor signaling was required for epithelial cell growth, functional differentiation, and morphogenesis of immature MECs, and the survival of terminally differentiated MECs. Finally, ErbB4 expression did not interfere with functional differentiation and apoptosis of normal MECs.

Uncoupling of PI3K from ErbB3 Impairs Mammary Gland Development but Does Not Impact on ErbB2-Induced Mammary Tumorigenesis

“…Although the molecular basis for the lactation defect is unclear, reduced b-casein production in the ErbB3 D85 female indicates that ErbB3/PI3K signaling may also impact on the differentiation status of mammary epithelial cells. Because ErbB3 is a coreceptor for the heregulin growth factor family that plays an important role in mammary gland development (24,39), it is not unexpected that disruption of this ErbB3/PI3K axis would induce such a severe defect in mammary epithelial development. In contrast to the profound effects of loss of ErbB3/PI3K signaling on mammary development, the effect on ErbB2-driven tumorigenesis was modest.…”

The ERBB3 receptor in cancer and cancer gene therapy

“…178 Mammary gland ERBB3 expression in normal mammary gland and cells-Erbb3 levels were low in embryonic mammary tissue and increased during postnatal maturation, with evidence of activation via phosphorylation in mammary tissue during mid to late pregnancy in mice and high expression in both mammary ductal epithelial cells and stroma in pregnant rats. 179,180 ERBB3 was downregulated in functionally differentiated mammary epithelial cells. 179 In two nontransformed human mammary epithelial cell lines, H16N-2 and MCF-10A, NRG1β was strongly mitogenic and activated PI3K through ERBB2/ERBB3 heterodimer formation; 181 NRG1α was less effective.…”

“…179,180 ERBB3 was downregulated in functionally differentiated mammary epithelial cells. 179 In two nontransformed human mammary epithelial cell lines, H16N-2 and MCF-10A, NRG1β was strongly mitogenic and activated PI3K through ERBB2/ERBB3 heterodimer formation; 181 NRG1α was less effective. A significant, though weak, activation of PI3K was also observed after EGF stimulation and formation of an EGFR/ERBB2 heterodimer.…”

Unilateral once daily milking locally induces differential gene expression in both mammary tissue and milk epithelial cells revealing mammary remodeling

“…stage of mammary development in rodents (19,27). FN1 is involved in cell adhesion and migration and is known to modulate cell proliferation and induce matrix metalloproteinase (MMP) activity in the mammary tissue (46,55).…”