FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice
Sun-Young Lee, … , Ren Xu, Mina J. Bissell
Sun-Young Lee, … , Ren Xu, Mina J. Bissell
Published August 13, 2012
Citation Information: J Clin Invest. 2012;122(9):3211-3220. https://doi.org/10.1172/JCI60498.
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FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice

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 least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidate cancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancer cells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and in animals. 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 and anchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversion of 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 cancer patients’ poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism by which tumor cells can become EGFR-TKI resistant.

Authors

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

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Figure 3

FAM83A levels correlate directly with tumor growth rates and EGFR-TKI resistance in cultures and in vivo, as well as with patients’ prognosis.

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FAM83A levels correlate directly with tumor growth rates and EGFR-TKI re...
(A) Growth of tumors derived from T4-2 cells treated with scrambled or FAM83A siRNA and xenografted in nude mice (n = 8). (B) Growth of tumors derived from MDA-MB468 cells treated with control (luciferase) or FAM83A shRNA and xenografted in nude mice (n = 8). (C and D) Tumor growth of vector control and FAM83A-overexpressing T4-2 cells treated with oral gavage of sham (vehicle; B) or 30 mg/kg lapatinib (LP; C). FAM83A-overexpressing T4-2 cells were resistant to lapatinib treatment (n = 8). (E) FAM83A staining of sham- or lapatinib-treated vector control tumors as in C and D. Note the upregulation of endogenous FAM83A in lapatinib-treated tumors. (F) Survival of vector control, FAM83A-overexpressing, and FAM83A-depleted T4-2 cells and luciferase-sh control or FAM83A-depleted MDA-MB468 cells treated with AG1478 at different concentrations and measured by clonogenic assay after 10 days. Values are expressed relative to untreated. IC50 of AG1478 was as follows: T4-2 Ctrl, 10 nM; T4-2 FAM83A, 80 nM; T4-2 FAM83Ash, 6 nM; MDA-MB468 Ctrl, >1,000 nM; MDA-MB468 FAM83Ash, 7.5 nM. (G) Kaplan-Meier curve for a cohort of 159 breast cancer patient samples. High FAM83A expression correlated with poor prognosis (P < 0.05). *P < 0.05, **P < 0.01, ***P < 0.001, 2-way ANOVA with Bonferroni post-test.