Epigenetic activation of HORMAD1 in basal-like breast cancer: role in Rucaparib sensitivity.

Xian Wang,Ying Tan,Xixi Cao,Jin Ah Kim,Tianmeng Chen,Xiaosong Wang,Matthew Wexler,Yiheng Hu

doi:10.18632/oncotarget.25728

Abstract

Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype with features similar to the basal cells surrounding the mammary ducts. Treatment of patients with BLBC has been challenging due to the lack of well-defined molecular targets. Due to the clinical and pathological similarities of BLBC with BRCA-deficient breast cancers, the effectiveness of Poly (ADP-ribose) polymerase inhibitors (PARPi) has been tested in early phase clinical trials for patients with advanced BLBC, with limited clinical responses. Recently, it was reported that HORMAD1 overexpression sensitizes BLBC to HR-targeting agents by suppressing homologous recombination. Our independent analysis suggests that HORMAD1 is aberrantly overexpressed in about 80% of BLBC, and its expression in normal tissues is restricted to testis. Our experimental data suggests that HORMAD1 overexpression correlates with focal hypomethylation in BLBC. On the other hand, investigation of the Genomics of Drug Sensitivity in Cancer dataset revealed significantly reduced sensitivity of HORMAD1-overexpressing BLBC cell lines to Rucaparib, a commonly used PARPi. To further assess the role of HORMAD1 in PARPi sensitivity, we generated three HORMAD1-overexpressing xenograft models using the HORMAD1-low BLBC cell lines HCC1954, HCC1806, and BT20; we then subjected these xenograft models to Rucaparib treatment. Ectopic expression of HORMAD1 enhances tumor formations in two of these models, and significantly reduces sensitivity to Rucaparib in the HCC1954 model. Taken together, our data suggest that epigenetic activation of HORMAD1 by hypomethylation in BLBC may endow reduced sensitivity to Rucaparib treatment in some tumor models.

Highlights

Basal-like breast cancer (BLBC) possesses a aggressive clinical phenotype and a molecular subtype defined by an array of genes that are expressed by normal basal epithelial cells [1,2,3]
To verify the differential HORMAD1 expression in TNBC tissues compared to ER-positive tumors, we performed reverse transcription PCR (RT-PCR) using two primer sets specific for HORMAD1 in 14 ER positive and 46 triple-negative breast cancer tissues
We show that HORMAD1 is preferentially overexpressed in the BLBC subtype of breast cancer based on analysis of the The Cancer Genome Atlas (TCGA) and Metabric datasets

Summary

Introduction

Basal-like breast cancer (BLBC) possesses a aggressive clinical phenotype and a molecular subtype defined by an array of genes that are expressed by normal basal epithelial cells [1,2,3]. Derived from luminal progenitors, BLBCs share a similar gene expression pattern with normal basal stem cells. This suggests that common epigenetic alterations underlie this cancer subtype. Despite many efforts to profile and sequence BLBC www.oncotarget.com genomes, to date there are no defining genetic aberrations for this cancer subtype. There is no generally accepted definition for basal-like breast cancer: Some groups have used immunohistochemical marker panels to define BLBC, while others have used microarray-based expression profiling to define BLBC. The later idea is becoming more dominant alongside the rapid development of sequencing technology and bioinformatics

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Conclusion