ARSD, a novel ERα downstream target gene, inhibits proliferation and migration of breast cancer cells via activating Hippo/YAP pathway.

Advanced breast cancer (BC), especially basal like triple-negative BC (TNBC), is a highly malignant tumor without viable treatment option, highlighting the urgent need to seek novel therapeutic targets. Arylsulfatase D (ARSD), localized at Xp22.3, is a female-biased gene due to its escaping from X chromosome inactivation (XCI). Unfortunately, no systematic investigation of ARSD on BC has been reported. In this study, we observed that ARSD expression was positively related to ERα status either in BC cells or tissue specimens, which were associated with good prognosis. Furthermore, we found a set of hormone-responsive lineage-specific transcription factors, FOXA1, GATA3, ERα, directly drove high expression of ARSD through chromatin looping in luminal subtype BC cells. Opposingly, ARSD still subjected to XCI in TNBC cells mediated by Xist, CpG islands methylation, and inhibitory histone modification. Unexpectedly, we also found that ectopic ARSD overexpression could inhibit proliferation and migration of TNBC cells by activating Hippo/YAP pathway, indicating that ARSD may be a molecule brake on ERα signaling pathway, which restricted ERα to be an uncontrolled active status. Combined with other peoples' researches that Hippo signaling maintained ER expression and ER + BC growth, we believed that there should exist a regulative feedback loop formation among ERα, ARSD, and Hippo/YAP pathway. Collectively, our findings will help filling the knowledge gap about the influence of ARSD on BC and providing evidence that ARSD may serve as a potential marker to predict prognosis and as a therapeutic target.