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Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244283 | GEO | 2023/10/04

REPOSITORIES: GEO

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Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project4]

Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with no targeted therapeutics. The luminal androgen receptor (LAR), one of the six TNBC subtypes, constitutes 15% of TNBC and is enriched for AR and AR-target genes. Here, we show that a cohort of TNBC not only expresses full-length AR (AR-FL) at a much higher rate (~80%) than previously reported, but also expresses AR splice variants (AR-SVs) (~20%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK-STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation. Collectively, our work identifies and characterizes a pharmacologically targetable and previously unreported TNBC subtype predominantly in African American women and identifies a growth-promoting interaction between AR and JAK-STAT signaling.

2023-10-04 | GSE244282 | GEO

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [Spacial]

2023-10-31 | GSE245202 | GEO

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project3]

2023-10-04 | GSE244272 | GEO

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project2]

2023-10-04 | GSE244271 | GEO

Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype.

Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.

| S-EPMC10872270 | biostudies-literature

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [MDA-MB-453]

2023-10-31 | GSE245554 | GEO

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype

Project description:Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype

| PRJNA1022060 | ENA

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project3]

Project description:Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project3]

| PRJNA1022050 | ENA

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project4]

Project description:Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [project4]

| PRJNA1022064 | ENA

Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [Spacial]

Project description:Identification of a Therapeutically Targetable JAK-STAT Enriched Androgen Receptor (AR) and AR Splice Variant Positive Triple Negative Breast Cancer Subtype [Spacial]

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