Research ArticleCancer

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

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Science Signaling  20 Oct 2020:
Vol. 13, Issue 654, eaay6077
DOI: 10.1126/scisignal.aay6077

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An aspirin to make CSCs go away

Cancer stem cells (CSCs) are tumor cells with stem cell-like qualities that promote tumor progression, adaption to stress, and resistance to chemotherapy. Bhattacharya et al. found that aspirin targets CSCs in a way that may enhance the efficacy of chemotherapy in patients with basal-like breast cancers. In cultured CSCs from invasive breast tumors or in a mouse model of breast cancer, aspirin suppressed the synthesis of the drug efflux pump ABCG2 by relieving the repression of the transcription cofactor SMAR1 by pluripotency factors. Aspirin prevented doxorubicin-induced repression of SMAR1 and proliferation of CSCs, consequently enhancing the cytotoxicity of doxorubicin. Thus, in addition to its current use as an anti-inflammatory for inflammation-driven premalignancies and cancers, aspirin might also be used to target CSCs in invasive breast cancer.

Abstract

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

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