HER2-positive breast cancer cells expressing elevated FAM83A are sensitive to FAM83A loss.

HER2-positive breast cancer (HER2+ BC) is an aggressive subtype with a poor prognosis. Although the antibody trastuzumab, which targets the HER2 growth factor receptor, has improved survival rates, patients often present with de novo resistance or acquire resistance after an initial response. Identifying new ways to target HER2 signaling will be critical for overcoming trastuzumab resistance. FAM83A is a novel oncogene identified by its ability to confer resistance to EGFR therapies, a receptor closely related to HER2. Moreover, a prior study identified hyper-tyrosine phosphorylated FAM83A in trastuzumab-resistant HER2+ BC. Here, we find that FAM83A expression is elevated in 36% of HER2+ BC tumors. In a panel of HER2+ BC cell lines, FAM83A expression is significantly increased in the trastuzumab-resistant derivatives relative to parental controls. shRNA-mediated ablation of FAM83A in the panel of HER2+ BC cell lines suppresses HER2+ BC cell growth in both 2D and 3D cell cultures, elevates apoptosis markers, and suppresses PI3K signaling. Growth inhibition following FAM83A knock-down, however, was independent of trastuzumab sensitivity, suggesting that FAM83A is a key signaling component in HER2+ BCs that could serve as a novel therapeutic target in both trastuzumab-resistant and trastuzumab-sensitive cancers.