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 3

Reduction of AR protein levels is conserved in skin cancer–derived CAFs.

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Reduction of AR protein levels is conserved in skin cancer–derived CAFs....
(A and B) Immunoblot analysis of AR and CSL levels in CAF strains derived from multiple skin SCCs and flanking unaffected skin from matched (A) or unmatched donors (B). The blots were sequentially probed with antibodies against AR, CSL, and β-actin. (C and D) Immunoblot analysis of AR (C and D) and CSL (D) levels in multiple CAF strains derived from BCC (C) and melanoma (D) lesions versus a reference set of HDF strains. In the case of melanoma-derived CAFs, samples were run in parallel with an extract of melanoma cells (SK-MEL-23), and the blot was also probed with antibodies against the melanocyte/melanoma marker MITF, to verify that CAF cells were stromal derived (MITF negative). Additionally, DNA sequencing analysis showed oncogenic BRAF or NRAS mutations in the excised melanomas but not in the CAFs derived from these lesions (data not shown). (E and F) Quantification of immunofluorescence analysis of AR expression in multiple CAF strains derived from skin SCC (E) or melanoma (F) versus a reference set of HDF strains. Values for each individual cell are indicated with mean ± SD. Twenty cells per strain were counted. Representative images are shown in Supplemental Figure 2A. n(HDF strains) = 3, n(SCC-derived CAF strains) = 3, n(melanoma-derived CAF strains) = 5; ***P < 0.005, 2-tailed unpaired t test.