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Uncovering of Intratumoral Androgen -Dependent Molecular Signature for Better Breast Cancer Prognosis [RNA-Seq]

ABSTRACT: The role of androgens in breast cancer (BC) was defined by correlating circulating androgens to clinical variables. Considering that intratumoral hormonal milieu is the critical determinant of BC characteristics, correlating intratumoral, androgens and their downstream transcriptome, a measure of free unbound androgen function, will provide clarity on androgen action in BC. Preclinical studies have shown that androgens and their receptor, androgen receptor (AR), have complex function in BC functioning as tumor suppressor in estrogen receptor (ER)-positive BC and oncogene in triple negative BC (TNBC). To obtain clarity on the role of androgens in BC, we measured intratumoral androgens and transcriptome in patient specimens. Intratumoral androstenedione (A4), but not dehydroepiandrosterone nor testosterone, from 62 BC specimens correlated with 1388 genes. A4-correlated genes classified patients into low, intermediate, and high A4 levels. A4-high patients had lower tumor cell proliferation, stage, and grade, and longer survival. A4-low patients’ tumors belonged to TNBC subtype and comprised of African American women. High intratumoral A4 levels extended the survival of ER+ve patients. These results were verified using TCGA and an independent clinical cohort. Using machine learning, we refined 1388 genes to a robust 90-gene A4-driven predictive signature. This signature strongly correlated with A4 levels and accurately predicted important clinical properties including tumor aggressiveness and survival outcomes. Collectively, we have discovered a tumor suppressor role for androgens, especially A4, in BC and identified a 90-gene A4 signature that offers a powerful tool for predicting A4 levels and related prognostic markers, which are otherwise challenging to assess.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329391 | GEO | 2026/09/04

REPOSITORIES: GEO

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Project description:Background: High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy, exhibiting marked heterogeneity that complicates treatment. The implications of intratumoral androgen metabolism and signalling, particularly involving 11-oxygenated androgens, in HGSOC remains poorly understood. Methods: We analysed expression of key androgen-metabolizing enzymes and androgen receptor (AR) in relation to tumor site, chemotherapy response, and survival using two public HGSOC cohorts. Quantitative gene expression and steroid metabolism assays upon incubation with classic and 11-oxyandrogen precursors were performed in six HGSOC cell lines and one normal ovarian epithelial line. Untargeted transcriptomic and metabolomic profiling were performed to assess cellular responses to potent classic and 11-oxygenated androgens in the AR-positive OVSAHO cell line. Results: Differential expression of steroid-metabolizing enzymes and AR were observed between primary and metastatic tumors and chemo-sensitive and chemo-resistant tumors. Higher intra-tumoral expression of HSD11B2, HSD17B2, and AR correlated with improved survival, whereas elevated PAPSS1/2 and HSD17B4 predicted poorer outcomes. In vitro, classic androgen precursors showed limited conversion to bioactive androgens and did not generate 11-oxyandrogens. In contrast, 11-oxyandrogen precursors were efficiently converted to the potent AR agonist 11KT in chemo-sensitive HGSOC cell lines, but not in chemo-refractory or control lines. Potent classic and 11-oxyandrogens induced stress-adaptive and proliferative transcriptional responses and reduced intracellular amino acid content. These changes were associated with a trend toward reduced cell proliferation. Conclusions: Our findings offer mechanistic insight into local androgen and 11-oxyandrogen metabolism and signalling in HGSOC and reveal steroid-induced cellular vulnerabilities that may synergize with chemotherapy or molecularly targeted therapies. These results further support the therapeutic potential of modulating steroid pathways in HGSOC.

Project description:Androgens drive the onset and progression of prostate cancer (PCa) by modulating androgen receptor (AR) transcriptional activity. Although several microarray-based studies have identified androgen-regulated genes, here we identify in-parallel global androgen-dependent changes in both gene and alternative mRNA isoform expression by exon-level analyses of the LNCaP transcriptome. While genome-wide gene expression changes correlated well with previously-published studies, we additionally uncovered a subset of 226 novel androgen-regulated genes. Gene expression pathway analysis of this subset revealed gene clusters associated with, and including the tyrosine kinase LYN, as well as components of the mTOR (mammalian target of rapamycin) pathway, which is commonly dysregulated in cancer. We also identified 1279 putative androgen-regulated alternative events, of which 325 (~25%) mapped to known alternative splicing events or alternative first/last exons. We selected 30 androgen-dependent alternative events for RT-PCR validation, including mRNAs derived from genes encoding tumour suppressors and cell cycle regulators. Of seven positively-validating events (~23%), five events involved transcripts derived from known AR gene targets. In particular, we found a novel androgen-dependent mRNA isoform derived from an alternative internal promoter within the TSC2 tumour suppressor gene, which is predicted to encode a protein lacking an interaction domain required for mTOR inhibition. We confirmed that expression of the alternative TSC2 mRNA isoform was directly regulated by androgens. Furthermore, by chromatin immunoprecipitation, we observed recruitment of AR to the alternative promoter region at early timepoints following androgen stimulation, which correlated with expression of alternative transcripts. Together, our data suggest that alternative mRNA isoform expression might mediate the cellular response to androgens, and may have roles in clinical PCa. Total 8 samples were analysed. 4 control (LNCaP cells grown in RPMI-1640 media with charcoal-stripped 10% FBS devoid of steroids) and 4 treatment (LNCaP cells grown in media devoid of steroid, and subsequently treated with 10nM R1881 synthetic androgen analogue for 24 hours).

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Uncovering of Intratumoral Androgen -Dependent Molecular Signature for Better Breast Cancer Prognosis [RNA-Seq]

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