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Hedgehog-mesenchyme gene signature identifies bi-modal prognosis in Luminal and Basal breast cancer sub-types

Abstract

Hedgehog signaling (Hh) has been shown to be hyper-activated in several cancers. However, active Hh signaling can promote or inhibit tumor growth, thus identification of markers beyond main canonical Hh target genes are needed to improve patient selection and clinical outcome in response to Hh inhibitors. Cancer-associated fibroblast (CAFs) have been linked with tumor progression and beneficial response to Hh inhibitors. Thus, we hypothesized that genes associated with Hh-activated CAFs can be used for stratification of tumors that will benefit from Hh inhibitors. In this work, we evaluated a 15-gene fingerprint that combines Hh and mesenchymal genes associated to CAFs phenotype to profile breast cancer sub-types based on gene expression patterns among clustered groups. About 3,800 cancer samples were evaluated using random forest models and linear discriminant analysis to sort breast cancer by subtypes and therapeutic approach. Results showed that the Hh-mesenchyme gene fingerprint has a highly sensitive and differential expression pattern among basal and luminal A sub-groups. Basal samples with high levels of Hh target genes had better prognosis than Luminal A samples. Luminal A samples with tendency towards Hh signaling suppression had higher overall and disease-free survival rates particularly if deprived of hormone therapy. Hh transcriptional repressor GLI3 and signaling activator SMO were the top 2 genes to discriminate among samples with active Hh signaling in human breast cancer subtypes and Hh-inhibitor resistant tumors. Caveolin-1 (CAV1), a gene associated to low expression in CAFs, shows strong correlation with active Hh signaling and discrimination among survival curves in Luminal A patients with active or inactive Hh signaling. Our data suggests that CAV1 is an important gene for monitoring Hh inhibition in tumors and supports further stratification by hormone therapy status prior to use of Hh inhibitors.

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Supplementary files

Publication details

The article was received on 10 Jul 2017, accepted on 07 Sep 2017 and first published on 07 Sep 2017


Article type: Paper
DOI: 10.1039/C7MB00416H
Citation: Mol. BioSyst., 2017, Accepted Manuscript
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    Hedgehog-mesenchyme gene signature identifies bi-modal prognosis in Luminal and Basal breast cancer sub-types

    W. Torres-Garcia and M. Domenech, Mol. BioSyst., 2017, Accepted Manuscript , DOI: 10.1039/C7MB00416H

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