HER2 (or erbB2) is a receptor tyrosine kinase in the epidermal growth factor receptor (EGFR) family that is overexpressed in approximately 30% of human breast cancers (BrCa) where overexpression correlates with a poor prognosis. However, the consequences of HER2 expression in normal mammary epithelia, where it is expressed physiologically at low levels, are not understood. We investigated whether the HER2-initiated pathways found in BrCa cells played a role in the development of the mammary gland. We studied the ability of a primary human mammary epithelial (HME) cell to undergo morphological changes and form polarized branching structures in Matrigel. We show that there was an increase in both total and tyrosine phosphorylated HER2 levels in normal HME cells that exhibited changes in colony morphology. A HER2-overexpressing cell line in Matrigel also produced differential colony morphogenesis compared to vector control. The morphology change included multi-cellular branches that had a ductal appearance in hematoxylin and eosin (H&E)-stained thick sections and in electron micrographs and secreted a milk-like substance. Using inhibitors and constitutively activated mutants, we determined that phosphoinositide 3-kinase (PI3K) is necessary but not sufficient, and that AKT is both necessary and sufficient to produce the morphological changes associated with overexpression of HER2. Our data suggest that HER2 signaling, via AKT, plays a role in normal mammary gland development.
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