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- Title
FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice.
- Authors
Sun-Young Lee; Meier, Roland; Furuta, Saori; Lenburg, Marc E.; Kenny, Paraic A.; Xu, Ren; Bissell, Mina J.
- 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.
- Subjects
PROTEIN-tyrosine kinase inhibitors; EPIDERMAL growth factor receptors; BREAST cancer; CANCER cells; LABORATORY mice; GENE expression; CELL proliferation
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 9, p3211
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI60498