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

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

doi:10.1172/jci99159

Cited by 45 publications

(47 citation statements)

References 48 publications

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“…A complex relationship exists between NOTCH1 and CSL activity in HDFs and CAFs. CSL functions as a constitutive negative repressor of a large battery of CAF effector genes, which are all induced by decreased CSL expression as it occurs at early steps of CAF activation 3,17,23,24 . Separately from its role in transcription, CSL is essential for maintenance of genomic stability as part of a telomere protective complex that is lost in CAFs 19 .…”

Section: Resultsmentioning

confidence: 99%

“…The NOTCH/CSL signaling pathway plays a key role in early steps of CAF activation. Loss of CSL transcription repressive function leads to concomitant induction of stromal fibroblast senescence and up-regulation of a large battery of CAF-effector genes 3,23,24 . This can be the combined result of down-modulation of CSL expression by exogenous pro-carcinogenic insults, such as UVA or smoke exposure 17,31 , and of NOTCH activation, which converts CSL from a repressor into an activator of transcription 3 .…”

Section: Discussionmentioning

confidence: 99%

“…For in vivo approaches, skin-derived SCC13 cells 35 were infected with a DsRed2-expressing lentivirus 3 . 2D co-culture assays in CAFs were performed as in Clocchiatti et al 23 .…”

Section: Methodsmentioning

confidence: 99%

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NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin

et al. 2020

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Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment. Genomic alterations in these cells remain a point of contention. We report that CAFs from skin squamous cell carcinomas (SCCs) display chromosomal alterations, with heterogeneous NOTCH1 gene amplification and overexpression that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 amplification is expanded by chronic UVA exposure, to which CAFs are resistant. The advantage conferred by NOTCH1 amplification and overexpression can be explained by NOTCH1 ability to block the DNA damage response (DDR) and ensuing growth arrest through suppression of ATM-FOXO3a association and downstream signaling cascade. In an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer/stromal cells expansion. Here we show that NOTCH1 gene amplification and increased expression in CAFs are an attractive target for stroma-focused anti-cancer intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin

et al. 2020

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“…Experimental data show that not only epithelial cells but also CAFs are under sex hormone control, with variable results depending on the tissue [20,21]. In mouse models, AR loss in dermal fibroblasts enhances tumourigenicity of SCC and melanoma cells [22], and AR expression is downregulated in dermal fibroblasts underlying premalignant skin cancer lesions as well as in CAFs from different skin cancer types [22]. Therefore, sex differences in the biology of non-sex-related cancers likely contribute to their differences in incidence and outcome [23,24] and this highlights the need to better understand the effect of sex-related genetic and hormonal factors on carcinogenesis in non-reproductive tissues.…”

Section: Sex Differences In Tumour Biologymentioning

confidence: 99%

Gender medicine and oncology: report and consensus of an ESMO workshop

et al. 2019

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Background: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. Design: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. Results: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. Conclusion: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.

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“…In addition, AR mutations are linked to disorders of male sexual differentiation and development termed androgen insensitivity syndromes (AIS) (Hughes et al 2012, Mongan et al 2015, Gibson et al 2018 and to the rare adult-onset hereditary neurodegenerative disorder known as spinal and bulbar muscular atrophy (SBMA or Kennedy's disease; OMIM #313200) (Spada et al 1991, Badders et al 2018, Cortes & La Spada 2018, Lieberman 2018, Pennuto & Rinaldi 2018. Finally, AR malfunction is also associated to androgenic alopecia or loss of scalp hair and skin malignancies (Ellis et al 2001, Clocchiatti et al 2018.…”

Section: Genetic Bases Of Drug Resistance In Prostate Cancermentioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

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Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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

Cited by 45 publications

References 48 publications

NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin

NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin

Gender medicine and oncology: report and consensus of an ESMO workshop

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

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