• Major finding: ER recruitment by FOXA1/2 protects against HCC, and AR recruitment promotes HCC.

  • Mechanism: EREs and AREs are found near the same FOXA1/2 binding sites in the liver.

  • Impact: Mutations in FOXA1/2 binding sites that impair ER binding may increase HCC risk in women.

Hepatocellular carcinoma (HCC) is sexually dimorphic in mammals, with males being much more likely to develop HCC than females. Because of the common roles of the forkhead box A (FOXA) transcription factors FOXA1 and FOXA2 in liver function and recruitment of estrogen receptor α (ER) and androgen receptor (AR) to cis-regulatory elements, Li and colleagues hypothesized that these proteins mediate the differential effects of estrogens and androgens on HCC development. Indeed, in mice in which both Foxa1 and Foxa2 had been specifically deleted in liver cells, the sexual dimorphism was completely reversed, with females developing multiple, large tumors and males exhibiting reduced tumor growth. Furthermore, Foxa1/2 loss led to a dramatic reduction in genome-wide ER and AR binding and reversed expression of FOXA target genes. The vast majority of genes differentially expressed in males and females were co-occupied by either AR or ER and FOXA1/2, and both estrogen response elements (ERE) and androgen response elements (ARE) clustered near FOXA binding sites. Collectively, these findings suggest that gender-specific co-regulation of a common set of target genes by FOXA1/2 and steroid hormone receptors underlies the sexual dimorphism observed in HCC. Multiple FOXA2 binding site mutations that impaired FOXA2 and ER binding and altered target gene expression were specifically identified in the livers of women with HCC, providing further evidence that disease-causing single-nucleotide polymorphisms may lie in cis-regulatory elements and that deregulated FOXA binding may play a role in human hepatocarcinogenesis.

Li Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 2012;148:72–83.

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