Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression.
Estrogen receptor-alpha positive (ER(+)) breast cancers comprise the majority of human breast cancers, but molecular mechanisms underlying this subtype of breast cancers remain poorly understood. Here, we show that ER(+) mammary luminal tumors arising in Tip30(-/-)MMTV-Neu mice exhibited increased enrichment of luminal progenitor gene signature. Deletion of the Tip30 gene increased proportion of mammary stem and progenitor cell populations, and raised susceptibility to ER(+) mammary luminal tumors in female Balb/c mice. Moreover, Tip30(-/-) luminal progenitors displayed increases in propensity to differentiate to mature ER(+) luminal cells and FoxA1 expression. Knockdown of FoxA1 expression in Tip30(-/-) progenitors by shRNA specific for FoxA1 reduced their differentiation toward ER(+) mature luminal cells. Taken together, our results suggest that TIP30 is a key regulator for maintaining ER(+) and ER(-)luminal pools in the mammary luminal lineage, and loss of it promotes expansion of ER(+) luminal progenitors and mature cells and ER(+) mammary tumorigenesis.
1] Department of Physiology, Michigan State University, East Lansing, MI, USA [2] Cancer Center, Southern Medical University, Guangzhou, China [3] Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Southern Medical University, Guangzhou, China.
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Chen
1] Department of Physiology, Michigan State University, East Lansing, MI, USA [2] Cancer Center, Southern Medical University, Guangzhou, China [3] Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Southern Medical University, Guangzhou, China.
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Li
1] Department of Physiology, Michigan State University, East Lansing, MI, USA [2] Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
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Gao
Department of Physiology, Michigan State University, East Lansing, MI, USA.
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Hollern
1] Department of Physiology, Michigan State University, East Lansing, MI, USA [2] Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA.
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Williams
1] Department of Physiology, Michigan State University, East Lansing, MI, USA [2] Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Southern Medical University, Guangzhou, China.
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Liu
Department of Physiology, Michigan State University, East Lansing, MI, USA.
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VanSickle
Department of Physiology, Michigan State University, East Lansing, MI, USA.
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Andrechek
Department of Physiology, Michigan State University, East Lansing, MI, USA.
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Zhang
Department of Physiology, Michigan State University, East Lansing, MI, USA.
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Yang
1] Cancer Center, Southern Medical University, Guangzhou, China [2] Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Southern Medical University, Guangzhou, China.
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Luo
1] Department of Physiology, Michigan State University, East Lansing, MI, USA [2] Cell and Molecular Biology Program, Michigan State University, East Lansing, MI, USA.
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Xiao
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018734:Genes, erbB-2; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D011960:Receptors, Estrogen; D012097:Repressor Proteins; C525546:Tip30 protein, mouse; D025521:Tumor Suppressor Proteins