ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer

Abstract

assisted with the initial computational analyses. H.Z. helped with the mouse in vivo experiment. K.J. assisted with patient selection. P.R. performed the nested control study, and assisted with patient sample procurement and survival analyses. P.R. and C.S. also performed the patient clinical annotation. J.S.R. viewed the FFPE slides, performed the laser microdissection and provided intellectual support. C.K. supervised the SWI/SNF complex ChIP-seq, helped with the SWI/SNF complex ChIP-seq data interpretation and provided intellectual insights.

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

“…Case ERLR_20 harbored an enriched nonsense mutation in ARID1A. ARID1A alterations are associated with more unfavorable tumor features in breast cancer, and has recently been shown to determine luminal identify and therapy response in ER-positive tumors-consistent with the more basal-like transcriptional features we observe with ESR1-depleted recurrences [37][38][39][40] . A single recurrent cancer (ERLR_01_R1) showed enrichment of three somatic hotspot PIK3CA mutations (E542K, Q546K, E726K), suggesting strong MAPK signaling selection within that particular tumor and coincident with recent reports of multiple mutations occurring in individual cancer genes in advanced cancers 41 .…”

Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression

“…The BRG1 and BAF57 proteins have transcription initiation roles and interact with ERα, similarly to the INO80 protein complex [88][89][90]97]. ARID1A is a key protein in the basal cell transition of breast cancer, and it plays a pivotal role in ERα-induced gene transcription [98].…”

“…The chromatin remodeling complexes are also exquisite players in the development of breast cancer. For instance, ARID1A, as a member of the SWI/SNF chromatin remodeling complex, interacts with ERα at the ERE sites in the genome and prevents the luminal cells from transitioning into basal cells [98]. By contrast, the genetic deletion of ARID1A blocks the binding of ERα to the DNA, which promotes basal cell development [98].…”

“…For instance, ARID1A, as a member of the SWI/SNF chromatin remodeling complex, interacts with ERα at the ERE sites in the genome and prevents the luminal cells from transitioning into basal cells [98]. By contrast, the genetic deletion of ARID1A blocks the binding of ERα to the DNA, which promotes basal cell development [98]. Together, these results suggest that the interaction between ERα and ARID1A may provide an effective platform for maintaining the endocrine therapeutic response in ERα-positive breast cancer.…”

Identification of Antiestrogen‐Bound Estrogen Receptor α Interactomes in Hormone‐Responsive Human Breast Cancer Cell Nuclei

“…By epigenome CRISPR-CAS9 knockout, ARID1A was included as a top candidate whose loss determines fulvestrant-resistance. [25,26] Moreover, several other ER molecular partners, including ER itself, represent essential genes for BC cell survival, such as MED12, SMARCB1, SMARCD1, and NF1, among others. [27,28] When combined, these findings both recapitulate known effects of the ER ligands on ER functions in BC, such as in the case of FOXA1 and GATA3 for example, [29,30] and highlight additional features, suggested by several novel receptor partners found, likely to be involved in BC genome vulnerabilities and resistance to endocrine therapy.…”