FAM3C in cancer-associated adipocytes promotes breast cancer cell survival and metastasis.

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 (CAAs) as a key regulator of tumor progression. FAM3C overexpression in cultured adipocytes significantly reduced cell death in both adipocytes and co-cultured 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 TGF-β signaling from breast cancer cells and was reduced upon treatment with a TGF-β-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 to those with non-metastatic 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.