ASH2L induces tamoxifen resistance via H3K4me3 dependent ITGA6/ERK signaling in ER-positive breast cancer

TL;DR

This study shows how ASH2L causes tamoxifen resistance in breast cancer and suggests combining tamoxifen with ERK inhibitors could help patients with ASH2L overexpression.

Contribution

The study identifies ASH2L as a driver of tamoxifen resistance through H3K4me3-dependent ITGA6/ERK signaling in ER-positive breast cancer.

Findings

ASH2L overexpression correlates with poor prognosis in tamoxifen-treated ER-positive breast cancer patients.

ASH2L induces tamoxifen resistance and cancer stem cell activity via ITGA6/ERK signaling.

Combining tamoxifen with ERK inhibition overcomes resistance in vitro and in vivo.

Abstract

Tamoxifen resistance remains a significant obstacle in oestrogen receptor (ER)-positive breast cancer. The function of absent, small, or homeotic 2-like protein (ASH2L) at chr8p11.23 in breast cancer is not entirely understood.

Survival analysis according to ASH2L expression was examined using METABRIC (n = 968) and KM plotter (n = 150). ASH2L-mediated tamoxifen resistance and CSC activity were evaluated through in vitro assays, including SRB, colony formation, tumour sphere formation, and FACS, and in vivo xenograft models. RNA-seq and ChIP-qPCR were performed to elucidate the underlying mechanism.

High ASH2L amplification correlated with poor prognosis in tamoxifen-treated ER-positive breast cancer patients. ASH2L induces tamoxifen resistance and promotes CSC activity through ITGA6/ERK signalling in an H3K4me3-dependent manner. Mechanistically, ASH2L is recruited to HIF2A and ITGA6 promoters, enhancing H3K4me3 and H3K27ac and reducing HDAC1 and H3K27me3, thereby activating ERK signalling. Genetic or pharmacological inhibition of ASH2L, ITGA6, or ERK abolished ASH2L-induced CSC activity. Although ERK inhibition alone did not rescue tamoxifen resistance, its combination with tamoxifen overcame resistance in vitro and in vivo.

ASH2L promotes tamoxifen resistance and CSC activity through ITGA6/ERK signalling. Combination therapy with tamoxifen and an ERK inhibitor may be a promising strategy for ER-positive breast cancer patients with ASH2L overexpression.

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