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

作者：Dimri Manjari; Naramura Mayumi; Duan Lei; Chen Jing; Ortega Cava Cesar; Chen Gengsheng; Goswami Rasna; Fernandes Norvin; Gao Qingshen; Dimri Goberdhan P; Band Vimla; Band Hamid^*

来源：Cancer Research, 2007, 67(9): 4164-4172.

DOI：10.1158/0008-5472.CAN-06-2580

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.

• 出版日期2007-5-1
• 单位西北大学