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.
|Journal||Cell Death and Disease|
|State||Published - 2014|
Bibliographical noteFunding Information:
Acknowledgements. We are grateful to Jill Pecha for backcrossing Tip30 knockout gene into Balb/c mice and Ying Qin for histological examination of preneoplastic lesions and tumors. This work was supported by NIDDK grant DK066110-01 and DOD grant W81XWH-08-1-0377 to H Xiao, Komen grant KG110510 and NCI grant 1R01CA160514-01A1 to E Andrechek and Guangdong Natural Science Foundation grant (10151051501000050) to A Li F Chen and A Li were supported in part by fellowships from Nanfang Hospital, China. M Williams was supported by NIH 5T32GM92715 training grant. CY was supported by National Institute of Health (1R01ES017777-01A1).
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research