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

Details

Serval ID
serval:BIB_DB6A4F3B1607
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation.
Journal
The Journal of clinical investigation
Author(s)
Clocchiatti A., Ghosh S., Procopio M.G., Mazzeo L., Bordignon P., Ostano P., Goruppi S., Bottoni G., Katarkar A., Levesque M., Kölblinger P., Dummer R., Neel V., Özdemir B.C., Dotto G.P.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
03/12/2018
Peer-reviewed
Oui
Volume
128
Number
12
Pages
5531-5548
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Animals, Cancer-Associated Fibroblasts/metabolism, Cancer-Associated Fibroblasts/pathology, Cell Line, Tumor, Female, Humans, Mice, Mice, Inbred NOD, Neoplasm Proteins/genetics, Neoplasm Proteins/metabolism, Receptors, Androgen/genetics, Receptors, Androgen/metabolism, Repressor Proteins/genetics, Repressor Proteins/metabolism, Skin Neoplasms/genetics, Skin Neoplasms/metabolism, Skin Neoplasms/pathology, Transcriptional Activation, Cancer, Dermatology, Oncology, Sex hormones, Skin cancer
Pubmed
Web of science
Open Access
Yes
Create date
13/11/2018 13:35
Last modification date
24/09/2019 6:11
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