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FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis
Open accessAbstract
FOXA1, estrogen receptor α (ERα) 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 ERα 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 ERα expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERα 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 ERα expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERα-positive breast cancers, at least in part, through its control of ERα expression.
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Cites
Generation of a functional mammary gland from a single stem cell
Shackleton, M., Vaillant, F., Simpson, K. J., Stingl, J., Smyth, G. K., Asselin-Labat, M.-L., Wu, L., Lindeman, G. J., & Visvader, J. E. (2006) · Nature · doi:10.1038/nature04372 · Cited by 2,005
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Pioneer transcription factors: establishing competence for gene expression
Zaret, K. S., & Carroll, J. S. (2011) · Genes & Development · doi:10.1101/gad.176826.111 · Cited by 1,589
Forkhead box proteins: tuning forks for transcriptional harmony.
Lam, E. W.-F., Brosens, J. J., Gomes, A. R., & Koo, C.-Y. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3539 · Cited by 684
Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland
Shehata, M., Teschendorff, A., Sharp, G., Novcic, N., Russell, I. A., Avril, S., Prater, M., Eirew, P., Caldas, C., Watson, C. J., et al. (2012) · Breast Cancer Research · doi:10.1186/bcr3334 · Cited by 306
Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene?
Hickey, T. E., Robinson, J. L. L., Carroll, J. S., & Tilley, W. D. (2012) · Molecular Endocrinology · doi:10.1210/me.2012-1107 · Cited by 289
Stem Cells and the Differentiation Hierarchy in Mammary Gland Development
Fu, N. Y., Nolan, E., Lindeman, G. J., & Visvader, J. E. (2020) · Physiological Reviews · doi:10.1152/physrev.00040.2018 · Cited by 267
Self-citationTakaku, M., Grimm, S. A., Shimbo, T., Perera, L., Menafra, R., Stunnenberg, H. G., Archer, T. K., Machida, S., Kurumizaka, H., & Wade, P. A. (2016) · Genome Biology · doi:10.1186/s13059-016-0897-0 · Cited by 151
Yang, Y. A., Zhao, J. C., Fong, K.-W., Kim, J., Li, S., Song, C., Song, B., Zheng, B., He, C., & Yu, J. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw498 · Cited by 69
Metadata
- Authors
- Bernardo, G. M., Lozada, K. L., Miedler, J. D., Harburg, G., Hewitt, S. C., Mosley, J. D., Godwin, A. K., Korach, K. S., Visvader, J. E., Kaestner, K. H., Abdul-Karim, F. W., Montano, M. M., & Keri, R. A.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2010-06-15
- Volume
- 137
- Issue
- 12
- Pages
- 2045-2054
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2055131544
- Cited by
- 247
- References
- 1
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- green
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