Abstract
PES1 promotes breast cancer growth by differentially regulating ERα and ERβ.
Major finding: PES1 promotes breast cancer growth by differentially regulating ERα and ERβ.
Mechanism: PES1 enhances ERα activity and protein stability but has the opposite effect on ERβ.
Impact: PES1 may be an effective therapeutic target to suppress ERα -positive tumor growth.
Estrogen-mediated regulation of breast cancer is dependent on signaling through estrogen receptors (ER) α and β, which have been shown to function antagonistically. Increased ERα expression promotes tumor growth, whereas ERβ inhibits ERα-stimulated proliferation and is downregulated in breast tumors. Cheng and colleagues investigated the mechanisms that control the balance of these 2 proteins and identified Pescadillo (PES1), an estrogen-induced protein that is overexpressed in breast cancer, as a critical mediator of ERα-driven tumorigenesis. Microarray analysis demonstrated that PES1 regulated the expression of estrogen-responsive genes involved in DNA replication and cell-cycle progression, many of which are activated by ERα and repressed by ERβ. In addition, PES1 specifically enhanced ERα homodimerization and recruitment to estrogen-responsive promoters while decreasing these activities of ERβ, indicating that PES1 differentially regulates ERα and ERβ transcriptional activity in breast cancer. This effect was mediated via modulation of ER protein levels through the E3 ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP). PES1 expression stabilized ERα protein but promoted CHIP-driven ubiquitination and proteasomal degradation of ERβ, suggesting that PES1 may facilitate breast cancer growth via increased ERα signaling and decreased ERβ signaling. Consistent with this idea, PES1 depletion impaired estrogen-stimulated breast cancer cell proliferation and anchorage-independent growth in vitro and diminished estrogen-dependent tumor growth in vivo. Conversely, PES1 expression was sufficient to transform normal human mammary epithelial cells in soft agar assays. Furthermore, PES1 expression was positively correlated with ERα and negatively correlated with ERβ expression in human breast cancer samples. These results support a critical role for PES1 in breast cancer pathogenesis and suggest that current endocrine therapy might be improved by targeted inhibition of this protein.
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