Dataset Information

AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer.

ABSTRACT: Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.

SUBMITTER: Kubli SP

PROVIDER: S-EPMC6397541 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer.

Kubli Shawn P SP Bassi Christian C Roux Cecilia C Wakeham Andrew A Göbl Christoph C Zhou Wenjing W Jafari Soode Moghadas SM Snow Bryan B Jones Lisa L Palomero Luis L Thu Kelsie L KL Cassetta Luca L Soong Daniel D Berger Thorsten T Ramachandran Parameswaran P Baniasadi Shakiba P SP Duncan Gordon G Lindzen Moshit M Yarden Yosef Y Herranz Carmen C Lazaro Conxi C Chu Mandy F MF Haight Jillian J Tinto Paul P Silvester Jennifer J Cescon David W DW Petit Anna A Pettersson Sven S Pollard Jeffrey W JW Mak Tak W TW Pujana Miguel A MA Cappello Paola P Gorrini Chiara C

Proceedings of the National Academy of Sciences of the United States of America 20190207 9

Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuc ...[more]

PMID: 30733286

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Project description:Background: Epigenetic dysregulation via aberrant DNA methylation has gradually become recognized as an efficacious signature for predicting tumor prognosis and response to therapeutic targets. However, reliable DNA methylation biomarkers describing tumorigenesis remain to be comprehensively explored regarding their prognostic and therapeutic potential in breast cancer (BC). Methods: Whole-genome methylation datasets integrated from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were profiled (n = 1,268). A three-stage selection procedure (discovery, training, and external validation) was utilized to screen out the prominent biomarkers and establish a robust risk score from more than 300,000 CpG sites after quality control, rigorous filtering, and reducing dimension. Moreover, gene set enrichment analyses guided us to systematically correlate this epigenetic risk score with immunological characteristics, including immunomodulators, anti-cancer immunity cycle, immune checkpoints, tumor-infiltrating immune cells and a series of signatures upon modulating components within BC tumor microenvironment (TME). Multi-omics data analyses were performed to decipher specific genomic alterations in low- and high-risk patients. Additionally, we also analyzed the role of risk score in predicting response to several treatment options. Results: A 10-CpG-based prognostic signature which could significantly and independently categorize BC patients into distinct prognoses was established and sufficiently validated. And we hypothesize that this signature designs a non-inflamed TME in BC based on the evidence that the derived risk score is negatively correlated with tumor-associated infiltrating immune cells, anti-cancer immunity cycle, immune checkpoints, immune cytolytic activity, T cell inflamed score, immunophenoscore, and the vast majority of immunomodulators. The identified high-risk patients were characterized by upregulation of immune inhibited oncogenic pathways, higher TP53 mutation and copy number burden, but lower response to cancer immunotherapy and chemotherapy. Conclusion: Our work highlights the complementary roles of 10-CpG-based signature in estimating overall survival in BC patients, shedding new light on investigating failed events concerning immunotherapy at present.

Dataset Information

AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer.

Publications

AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer.

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