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Modeling Breast Cancer–Associated c-Src and EGFR Overexpression in Human MECs: c-Src and EGFR Cooperatively Promote Aberrant Three-dimensional Acinar Structure and Invasive Behavior

Divisions of ¹ Molecular Oncology and ² Cancer Biology, Evanston Northwestern Healthcare Research Institute, Department of Medicine, Feinberg School of Medicine; ³ Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois; and ⁴ Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Hamid Band and Vimla Band, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201. Phone: 224-364-7401/7501; Fax: 224-364-7402; E-mail: h-band{at}northwestern.edu and v-band{at}northwestern.edu.

Epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is overexpressed in as many as 60% cases of breast and other cancers. EGFR overexpression is a characteristic of highly aggressive molecular subtypes of breast cancer with basal-like and BRCA1 mutant phenotypes distinct from ErbB2-overexpressing breast cancers. Yet, EGFR is substantially weaker compared with ErbB2 in promoting the oncogenic transformation of nontumorigenic human mammary epithelial cells (human MEC), suggesting a role for cooperating oncogenes. Here, we have modeled the co-overexpression of EGFR and a biologically and clinically relevant potential modifier c-Src in two distinct immortal but nontumorigenic human MECs. Using a combination of morphologic analysis and confocal imaging of polarity markers in three-dimensional Matrigel culture together with functional analyses of early oncogenic traits, we show for the first time that EGFR and c-Src co-overexpression but not EGFR or c-Src overexpression alone unleashes an oncogenic signaling program that leads to hyperproliferation and loss of polarity in three-dimensional acinar cultures, marked enhancement of migratory and invasive behavior, and anchorage-independent growth. Our results establish that EGFR overexpression in an appropriate context (modeled here using c-Src overexpression) can initiate oncogenic transformation of nontumorigenic human MECs and provide a suitable in vitro model to interrogate human breast cancer–relevant oncogenic signaling pathways initiated by overexpressed EGFR and to identify modifiers of EGFR-mediated breast oncogenesis. [Cancer Res 2007;67(9):4164–72]

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