FAM3C in Cancer-Associated Adipocytes Promotes Breast Cancer Cell Survival and Metastasis

Abstract Adipose tissue within the tumor microenvironment (TME) plays a critical role in supporting breast cancer progression. In this study, we identified FAM3 metabolism-regulating signaling molecule C (FAM3C) produced by cancer-associated adipocytes (CAA) as a key regulator of tumor progression. FAM3C overexpression in cultured adipocytes significantly reduced cell death in both adipocytes and cocultured breast cancer cells while suppressing markers of fibrosis. Conversely, FAM3C depletion in CAAs resulted in adipocyte–mesenchymal transition (AMT) and increased fibrosis within the TME. Adipocyte FAM3C expression was driven by TGFβ signaling from breast cancer cells and was reduced upon treatment with a TGFβ-neutralizing antibody. FAM3C knockdown in CAAs early in tumorigenesis in a genetically engineered mouse model of breast cancer significantly inhibited primary and metastatic tumor growth. Circulating FAM3C levels were elevated in patients with metastatic breast cancer compared with those with nonmetastatic breast cancer. These results suggest that therapeutic inhibition of FAM3C expression levels in CAAs during early tumor development could be a promising approach in the treatment of patients with breast cancer. Significance: High FAM3C levels in cancer-associated adipocytes contribute to tumor-supportive niches and are tightly associated with metastatic growth, indicating that FAM3C inhibition could be beneficial for treating patients with breast cancer.