Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer

Zhaoyu Li, Geetu Tuteja, Jonathan Schug, Klaus H. Kaestner

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually dimorphic HCC is completely reversed in Foxa1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Coregulation of target genes by Foxa1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on Foxa1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC.

Original languageEnglish (US)
Pages (from-to)72-83
Number of pages12
JournalCell
Volume148
Issue number1-2
DOIs
StatePublished - Jan 20 2012
Externally publishedYes

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Liver Neoplasms
Sex Characteristics
Estrogen Receptors
Liver
Androgens
Hepatocellular Carcinoma
Estrogens
Diethylnitrosamine
Androgen Receptors
Gonadal Steroid Hormones
Polymorphism
Nucleotides
Genes
Binding Sites
Single Nucleotide Polymorphism
Rodentia
Incidence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. / Li, Zhaoyu; Tuteja, Geetu; Schug, Jonathan; Kaestner, Klaus H.

In: Cell, Vol. 148, No. 1-2, 20.01.2012, p. 72-83.

Research output: Contribution to journalArticle

Li, Z, Tuteja, G, Schug, J & Kaestner, KH 2012, 'Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer', Cell, vol. 148, no. 1-2, pp. 72-83. https://doi.org/10.1016/j.cell.2011.11.026
Li, Zhaoyu ; Tuteja, Geetu ; Schug, Jonathan ; Kaestner, Klaus H. / Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. In: Cell. 2012 ; Vol. 148, No. 1-2. pp. 72-83.
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