title: 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.affiliation: Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Roland
authors.initials: R
authors.lastname: Meier
authors.forename: Saori
authors.initials: S
authors.lastname: Furuta
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Paraic A
authors.initials: PA
authors.lastname: Kenny
authors.forename: Ren
authors.initials: R
authors.lastname: Xu
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C530220:FAM83A protein, human; D009363:Neoplasm Proteins; D011799:Quinazolines; D020032:Tyrphostins; D000077341:Lapatinib; C101044:RTKI cpd; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D000077156:Gefitinib