Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression.

F Chen, A Li, S Gao, D Hollern, M Williams, F Liu, E A VanSickle, E Andrechek, C Zhang, C Yang, R Luo, H Xiao

Cell death & disease 2014 May 22

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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.

Citation

F Chen, A Li, S Gao, D Hollern, M Williams, F Liu, E A VanSickle, E Andrechek, C Zhang, C Yang, R Luo, H Xiao. Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression. Cell death & disease. 2014 May 22;5:e1242