Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation
Andrea Clocchiatti, … , Berna C. Özdemir, G. Paolo Dotto
Andrea Clocchiatti, … , Berna C. Özdemir, G. Paolo Dotto
Published December 3, 2018; First published November 5, 2018
Citation Information: J Clin Invest. 2018;128(12):5531-5548. https://doi.org/10.1172/JCI99159.
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Research Article Dermatology Oncology

Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation

Abstract

The aging-associated increase of cancer risk is linked with stromal fibroblast senescence and concomitant cancer-associated fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signaling in this context. We have found downmodulated AR expression in dermal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses and dysplastic nevi) as well as in CAFs from the 3 major skin cancer types, squamous cell carcinomas (SCCs), basal cell carcinomas, and melanomas. Functionally, decreased AR expression in primary human dermal fibroblasts (HDFs) from multiple individuals induced early steps of CAF activation, and in an orthotopic skin cancer model, AR loss in HDFs enhanced tumorigenicity of SCC and melanoma cells. Forming a complex, AR converged with CSL/RBP-Jκ in transcriptional repression of key CAF effector genes. AR and CSL were positive determinants of each other’s expression, with BET inhibitors, which counteract the effects of decreased CSL, restoring AR expression and activity in CAFs. Increased AR expression in these cells overcame the consequences of CSL loss and was by itself sufficient to block the growth and tumor-enhancing effects of CAFs on neighboring cancer cells. As such, the findings establish AR as a target for stroma-focused cancer chemoprevention and treatment.

Authors

Andrea Clocchiatti, Soumitra Ghosh, Maria-Giuseppina Procopio, Luigi Mazzeo, Pino Bordignon, Paola Ostano, Sandro Goruppi, Giulia Bottoni, Atul Katarkar, Mitchell Levesque, Peter Kölblinger, Reinhard Dummer, Victor Neel, Berna C. Özdemir, G. Paolo Dotto

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Figure 1

Stromal AR levels are reduced in skin cancer fields.

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Stromal AR levels are reduced in skin cancer fields. (A) Top panels: Dou...
(A) Top panels: Double immunofluorescence (IF) analysis of topographically delimited stromal areas (numbered boxes) at various distances from the skin actinic keratosis (AK) lesion from patient 1, with anti-AR (red) and anti-vimentin (green) antibodies. Scale bar: 200 μm. Representative high-magnification IF images used for quantification of AR fluorescence signal in vimentin-positive fibroblasts cells. Scale bar: 20 μm. Bottom panels: Quantification of AR fluorescence signal in vimentin-positive cells within each delimited area from 2 different patients. Values for each individual cell are indicated with mean ± SD. Less than 5% of cells double-stained for vimentin and the CD68 macrophage marker in parallel sections (data not shown). The H&E staining and additional IF images are shown in Supplemental Figure 1A. (B) Top panels: Triple-IF analysis of topographically delimited stromal areas (numbered boxes) at various distances from dysplastic nevus lesion from patient 1, with anti–melan-A (red), anti-AR (magenta), and anti-vimentin (green) antibodies. Scale bar: 200 μm. Representative high-magnification IF images used for quantification of AR fluorescence signal in fibroblasts (vimentin-positive and melan-A–negative cells). Scale bar: 20 μm. Bottom panels: Quantification of AR fluorescence signal in the fibroblasts within each delimited area from 2 different patients. Values for each individual cell are indicated with mean ± SD. The immunohistochemical staining and additional IF images are shown in Supplemental Figure 1B.