TY - JOUR
T1 - Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer
AU - Li, Zhaoyu
AU - Tuteja, Geetu
AU - Schug, Jonathan
AU - Kaestner, Klaus H.
N1 - Funding Information:
We thank Drs. Jeff Albrecht, Linda Greenbaum, and Snorri Thorgeirsson for valuable comments on the manuscript. We acknowledge Alan Fox, Olga Smirnova, Karrie Brondell, Amber Riblett, James LaRossa, and Reina Aoki for their excellent technical support. We also thank Dr. Erik Knudsen for sharing his hepatocarcinogenesis protocol. This study was supported by the NIDDK (P01-DK049210 to KHK). Z.L. was supported by NSREC and JDRF postdoctoral fellowship awards. We thank the University of Pennsylvania Diabetes and Endocrinology Center (DERC) for the use of the Functional Genomics Core (P30-DK19525).
PY - 2012/1/20
Y1 - 2012/1/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862909192&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862909192&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.11.026
DO - 10.1016/j.cell.2011.11.026
M3 - Article
C2 - 22265403
AN - SCOPUS:84862909192
SN - 0092-8674
VL - 148
SP - 72
EP - 83
JO - Cell
JF - Cell
IS - 1-2
ER -