Abstract
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.