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FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis.

FOXA1, estrogen receptor alpha (ERalpha) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the morphogenesis of various organs, with ERalpha and GATA3 being established regulators of mammary gland development. Interdependency between these three factors in breast cancer and normal mammary development has been suggested, but the specific role for FOXA1 is not known. Herein, we report that Foxa1 deficiency causes a defect in hormone-induced mammary ductal invasion associated with a loss of terminal end bud formation and ERalpha expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERalpha and GATA3 deficiency, Foxa1 null glands form milk-producing alveoli, indicating that the defect is restricted to expansion of the ductal epithelium, further emphasizing the novel role for FOXA1 in mammary morphogenesis. Using breast cancer cell lines, we also demonstrate that FOXA1 regulates ERalpha expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERalpha-positive breast cancers, at least in part, through its control of ERalpha expression.

Pubmed ID: 20501593

Authors

  • Bernardo GM
  • Lozada KL
  • Miedler JD
  • Harburg G
  • Hewitt SC
  • Mosley JD
  • Godwin AK
  • Korach KS
  • Visvader JE
  • Kaestner KH
  • Abdul-Karim FW
  • Montano MM
  • Keri RA

Journal

Development (Cambridge, England)

Publication Data

June 26, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P01 DK049210
  • Agency: NCI NIH HHS, Id: P30 CA006927
  • Agency: NCI NIH HHS, Id: P30 CA043703
  • Agency: NCI NIH HHS, Id: R01 CA090398
  • Agency: NCI NIH HHS, Id: R01 CA092440
  • Agency: NIGMS NIH HHS, Id: T32 GM007250
  • Agency: NIGMS NIH HHS, Id: T32-GM0720

Mesh Terms

  • Breast
  • Breast Neoplasms
  • Epithelium
  • Estrogen Receptor alpha
  • Female
  • Hepatocyte Nuclear Factor 3-alpha
  • Humans
  • Morphogenesis