FoxM1 regulates mammary luminal cell fate.
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.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60607, USA.
Janai R
JR
Carr
Megan M
MM
Kiefer
Hyun Jung
HJ
Park
Jing
J
Li
Zebin
Z
Wang
Joel
J
Fontanarosa
Danielle
D
DeWaal
Dragana
D
Kopanja
Elizaveta V
EV
Benevolenskaya
Grace
G
Guzman
Pradip
P
Raychaudhuri
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D042361:Mammary Glands, Human / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; D016160:Retinoblastoma Protein; D000097584:DNA Methyltransferase 3B; C107585:FOXM1 protein, human; C491524:Foxm1 protein, mouse