Abstract
Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments.
Highlights
Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis
Using sequential chromatin immunoprecipitation (ChIP) assay, we showed that TET2– Forkhead box protein P1 (FOXP1) complex co-occupied in regulatory elements of Gata[3], Foxa[1], and Esr[1] genes (Fig. 2j)
Previous studies have revealed that TET2 can be a direct target of the Let-7adf cluster in LPSactivated macrophages[33], it can be suppressed by miR-29 in prostate cancer cells[9], and it is down-regulated by miR-22 in breast cancer cells34. miR-22, a microRNA that is associated with oncogenic signaling and overexpressed in high-grade breast tumors with poor clinical outcomes[26,34,35], directly targets ten-eleven translocation (TET)
Summary
Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and are often silenced by DNA methylation in aggressive breast cancers. Study has shown that repressed TET2 expression is linked to promoted epithelialmesenchymal-transition (EMT) phenotype and expansion of a breast cancer stem cell-like population with skewed asymmetric cell division in vitro[10]; the in vivo role that TET2 plays in regulation of mammary differentiation and tumorigenesis has yet to be determined. Using our established mammary-specific Tet[2] deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development via directing MaSC/progenitor cell to luminal lineage commitment in vivo. This study provides a role for TET2 that underlies breast cancer resistance to anti-estrogen treatments, and our in vivo Tet[2] deletion breast cancer mouse model will be a valuable tool for studying the associated mechanism(s) for development of anti-cancer therapies
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