A `one-two punch' therapy strategy to target chemoresistance in estrogen receptor positive breast cancer.

Translational Oncology
Feng ChiAndrea H Bild

Abstract

Cancer cell phenotypes evolve during a tumor's treatment. In some cases, tumor cells acquire cancer stem cell-like (CSL) traits such as resistance to chemotherapy and diminished differentiation; therefore, targeting these cells may be therapeutically beneficial. In this study we show that in progressive estrogen receptor positive (ER+) metastatic breast cancer tumors, resistant subclones that emerge following chemotherapy have increased CSL abundance. Further, in vitro organoid growth of ER+ patient cancer cells also shows that chemotherapy treatment leads to increased abundance of ALDH+/CD44+ CSL cells. Chemotherapy induced CSL abundance is blocked by treatment with a pan-HDAC inhibitor, belinostat. Belinostat treatment diminished both mammosphere formation and size following chemotherapy, indicating a decrease in progenitor CSL traits. HDAC inhibitors specific to class IIa (HDAC4, HDAC5) and IIb (HDAC6) were shown to primarily reverse the chemo-resistant CSL state. Single-cell RNA sequencing analysis with patient samples showed that HDAC targets and MYC signaling were promoted by chemotherapy and inhibited upon HDAC inhibitor treatment. In summary, HDAC inhibition can block chemotherapy-induced drug resistant phenotypes with ...Continue Reading

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Citations

May 25, 2021·Molecular Therapy Oncolytics·Guangshun SunYangbai Sun
Jul 27, 2021·Frontiers in Molecular Biosciences·Alejandra FernandezAmila Suraweera

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Datasets Mentioned

BETA
GSE147326

Methods Mentioned

BETA
RNA-Seq
FACS
flow cytometry
scRNA-Seq

Software Mentioned

GSEA
ssGSEA

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