Fluctuating levels of Fam3c in cancer-associated adipocytes contribute to breast cancer cell survival and metastasis

Abstract

Adipose tissue within the tumor microenvironment (TME) plays a critical role in breast cancer progression. Here, we identified FAM3 metabolism-regulating signaling molecule C (Fam3c), produced in cancer-associated adipocytes (CAAs), as a regulator of tumor development. Fam3c overexpression in cultured adipocytes significantly decreased cell death in both the adipocytes and co-cultured cancer cells, while inhibiting fibrosis. Conversely, Fam3c depletion in CAAs underwent adipocyte-mesenchymal transition (AMT) in association to increased fibrosis in the TME. Adipocyte Fam3c expression was driven by TGF-β signaling from breast cancer cells and was ameliorated upon treatment with a TGF-β-neutralizing antibody. Early Fam3c knockdown in CAAs in a tumorigenic mouse model led to significant inhibition of primary and metastatic tumor growth. Our results suggest that therapeutic inhibition of high levels of Fam3c in CAAs during early tumor development could be beneficial in treatment of breast cancer patients.