Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression

The incidence of certain types of extrahepatic cancers significantly increases in nonalcoholic fatty liver disease (NAFLD), the mechanisms of which are elusive. Here, we demonstrate that NAFLD is correlated with a higher risk of breast cancer in individuals with atypical hyperplasia and poor prognosis in patients with breast cancer. In mice, fatty liver exosomes are preferentially accumulated in adipocytes, and their enrichment in mammary adipocytes fosters a pro-tumor breast microenvironment. Adipocyte tropism is dictated by the binding of exosomal ErbB4 to neuregulin 4 (Nrg4). tRNA methyltransferase 10 homolog C (TRMT10C) in fatty liver exosomes translocates to mitochondria and inhibits Nd5 and Nd6 mRNA translation by inducing N¹-methyladenosine modifications in adipocytes. ND5 and ND6 reduction increases reactive oxygen species and consequently enhances free fatty acid release, which fuels tumor progression. Plasma ErbB4⁺ exosomes are an independent prognostic factor for patients with breast cancer and comorbid NAFLD. Collectively, we reveal a liver-breast metabolic remote interaction that drives cancer development.