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 2

AR expression is downmodulated in stromal fibroblasts of premalignant and malignant skin cancer lesions.

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AR expression is downmodulated in stromal fibroblasts of premalignant an...
(A–D) Quantification of immunofluorescence analysis of AR signal intensity in vimentin-positive stromal cells underlying actinic keratoses (AK) (A), dysplastic nevi (DN) (B), squamous cell carcinomas (SCC) (C), and basal cell carcinomas (BCC) (D) lesions versus flanking skin from multiple patients. For A and B quantification, the same lesions as in Figure 1A plus those of an additional patient were used for independent quantification of AR signal intensity in lesion-adjacent areas versus flanking skin. For C and D, stromal cells in SCC- and BCC-adjacent areas versus flanking skin of the same patients excised at the end of the surgical procedure (“dog ears”) were used for quantification. Values for each individual cell are indicated with mean ± SD. Representative lower- and higher-magnification images for SCC samples are shown in Supplemental Figure 1C. n(vimentin-positive cells per sample) = 25 for A and B, = 20 for C and D; ***P < 0.005, 2-tailed paired t test. (E) Fluorescence-guided laser capture microdissection (LCM) of fibroblast (PDGFRα-positive) cells from stroma of SCC lesions versus flanking skin of the same patients was analyzed by RT-qPCR for the indicated genes. Values for each patient are indicated as dots with mean ± SD. n(patients) = 6; ***P < 0.005, 2-tailed paired t test.