FoxM1 Regulates Mammary Luminal Cell Fate

• Published in: Cell reports (Cambridge) 2012-06, Vol.1 (6), p.715-729
• Main Authors: Carr, Janai R., Kiefer, Megan M., Park, Hyun Jung, Li, Jing, Wang, Zebin, Fontanarosa, Joel, DeWaal, Danielle, Kopanja, Dragana, Benevolenskaya, Elizaveta V., Guzman, Grace, Raychaudhuri, Pradip
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Binding Sites; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Differentiation; Cell Line, Tumor; Cell Lineage; Cell Proliferation; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation - genetics; DNA Methyltransferase 3B; Female; Forkhead Box Protein M1; Forkhead Transcription Factors - metabolism; GATA3 Transcription Factor - metabolism; Gene Knockdown Techniques; Humans; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Glands, Human - growth & development; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Pregnancy; Promoter Regions, Genetic - genetics; Retinoblastoma Protein - metabolism; Transcription, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.05.005

Elevated expression of FoxM1 in breast cancer correlates with an undifferentiated tumor phenotype and a negative clinical outcome. However, a role for FoxM1 in regulating mammary differentiation was not known. Here, we identify another function of FoxM1, the ability to act as a transcriptional repressor, which plays an important role in regulating the differentiation of luminal epithelial progenitors. Regeneration of mammary glands with elevated levels of FoxM1 leads to aberrant ductal morphology and expansion of the luminal progenitor pool. Conversely, knockdown of FoxM1 results in a shift toward the differentiated state. FoxM1 mediates these effects by repressing the key regulator of luminal differentiation, GATA-3. Through association with DNMT3b, FoxM1 promotes methylation of the GATA-3 promoter in an Rb-dependent manner. This study identifies FoxM1 as a critical regulator of mammary differentiation with significant implications for the development of aggressive breast cancers. [Display omitted] ► Increased FOXM1 leads to an expansion of mammary stem and progenitor pools ► Deletion of FoxM1 in virgin mice causes accumulation of the differentiated luminal cells ► FOXM1 acts as a transcriptional repressor of GATA-3 by promoting DNA methylation ► FOXM1 represses GATA-3 in an Rb-dependent manner Poorly differentiated breast cancers carry a negative patient prognosis due to high rates of metastasis, relapse, and resistance to therapy. Expression of GATA-3, a regulator of mammary luminal differentiation, is extinguished in high-grade tumors. A strong reciprocal relationship exists between expression of the oncogenic transcription factor FoxM1 and the tumor suppressor GATA-3 in breast cancers. Raychaudhuri and colleagues identify FoxM1 as a regulator of mammary differentiation with significant implications for the development and progression of high-grade breast cancer.