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

Manjari Dimri, Mayumi Naramura, Lei Duan, Jing Chen, Cesar Ortega-Cava, Gengsheng Chen, Rasna Goswami, Norvin Fernandes, Qingshen Gao, Goberdhan P. Dimri, Vimla Band, Hamid Band

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65 Citations (Scopus)

Abstract

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 non-tumorigenic 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.

Original languageEnglish (US)
Pages (from-to)4164-4172
Number of pages9
JournalCancer Research
Volume67
Issue number9
DOIs
StatePublished - May 1 2007

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Epidermal Growth Factor Receptor
Breast Neoplasms
Breast
Neoplastic Cell Transformation
Oncogenes
Protein-Tyrosine Kinases
Carcinogenesis
Epithelial Cells
Phenotype
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / 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.

In: Cancer Research, Vol. 67, No. 9, 01.05.2007, p. 4164-4172.

Research output: Contribution to journalArticle

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. / 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. In: Cancer Research. 2007 ; Vol. 67, No. 9. pp. 4164-4172.
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AU - Chen, Jing

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AU - Chen, Gengsheng

AU - Goswami, Rasna

AU - Fernandes, Norvin

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