FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice

Sun Young Lee, Roland Meier, Saori Furuta, Marc E. Lenburg, Paraic A. Kenny, Ren Xu, Mina J. Bissell

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Breast cancers commonly become resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at leastin part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measurereversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidatecancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancercells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and inanimals. Tumor cells that survived EGFR-TKI treatment in vivo had upregulated FAM83A levels. Additionally,FAM83A overexpression dramatically increased the number and size of transformed foci in cultured cells andanchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversionof the malignant phenotype, delayed tumor growth in mice, and rendered cells more sensitive to EGFR-TKI.Analyses of published clinical data revealed a correlation between high FAM83A expression and breast cancerpatients' poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF andPI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism bywhich tumor cells can become EGFR-TKI resistant.

Original languageEnglish (US)
Pages (from-to)3211-3220
Number of pages10
JournalJournal of Clinical Investigation
Volume122
Issue number9
DOIs
StatePublished - Sep 4 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Lee, S. Y., Meier, R., Furuta, S., Lenburg, M. E., Kenny, P. A., Xu, R., & Bissell, M. J. (2012). FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice. Journal of Clinical Investigation, 122(9), 3211-3220. https://doi.org/10.1172/JCI60498