Role of androgen receptor in prostatic neoplasia versus hyperplasia

Husain, Irma; Shukla, Saumya; Soni, Priyanka; Husain, Nuzhat

doi:10.4103/0973-1482.151429

Cited by 14 publications

(6 citation statements)

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“…The etiology of benign prostatic hyperplasia (BPH) and prostatic neoplasia, which can progress to PCa, is androgen-dependent, and reduction/obliteration of androgen action in the prostate has been the therapy of choice for BPH and PCa [ 148 ]. A recent study demonstrated that cases of PCa exhibited a higher staining intensity for AR when compared with BPH [ 149 ]. Remarkably, AR is a direct negatively regulated target of p53 [ 150 , 151 ].…”

Section: Introductionmentioning

confidence: 99%

Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Melnik

2017

Nutr Metab (Lond)

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There is accumulating evidence that milk shapes the postnatal metabolic environment of the newborn infant. Based on translational research, this perspective article provides a novel mechanistic link between milk intake and milk miRNA-regulated gene expression of the transcription factor p53 and DNA methyltransferase 1 (DNMT1), two guardians of the human genome, that control transcriptional activity, cell survival, and apoptosis. Major miRNAs of milk, especially miRNA-125b, directly target TP53 and complex p53-dependent gene regulatory networks. TP53 regulates the expression of key genes involved in cell homeostasis such as FOXO1, PTEN, SESN1, SESN2, AR, IGF1R, BAK1, BIRC5, and TNFSF10. Nuclear interaction of p53 with DNMT1 controls gene silencing. The most abundant miRNA of milk and milk fat, miRNA-148a, directly targets DNMT1. Reduced DNMT1 expression further attenuates the activity of histone deacetylase 1 (HDAC1) involved in the regulation of chromatin structure and access to transcription. The presented milk-mediated miRNA-p53-DNMT1 pathway exemplified at the promoter regulation of survivin (BIRC5) provides a novel explanation for the epidemiological association between milk consumption and acne vulgaris and prostate cancer. Notably, p53- and DNMT1-targeting miRNAs of bovine and human milk survive pasteurization and share identical seed sequences, which theoretically allows the interaction of bovine miRNAs with the human genome. Persistent intake of milk-derived miRNAs that attenuate p53- and DNMT1 signaling of the human milk consumer may thus present an overlooked risk factor promoting acne vulgaris, prostate cancer, and other p53/DNMT1-related Western diseases. Therefore, bioactive miRNAs of commercial milk should be eliminated from the human food chain.

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Section: Introductionmentioning

confidence: 99%

Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Melnik

2017

Nutr Metab (Lond)

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“…The prevalence of an AR low/negative expression pattern has generally been underappreciated, but has been observed in a number of experiments ( Table 2 ). [4] , [5] , [7] , [8] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] More generally, several studies have observed decreased AR protein expression/intensity in hormone-refractory patient metastases, 90 and in hormone-refractory patients when compared to normal, primary, or hormone-sensitive tissue. [86] , [91] CRPC subtypes that exhibit AR low/negative expression patterns (e.g.…”

Section: Resultsmentioning

confidence: 99%

Development and prevalence of castration-resistant prostate cancer subtypes

Vellky

Ricke

2020

Neoplasia

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Background Castration-resistant prostate cancer (CRPC) occurs when prostate cancer (CaP) progresses under therapy-induced castrate conditions. Several mechanisms have been proposed to explain this acquired resistance, many of which are driven by androgen receptor (AR). Recent findings, however, sub-classified CRPC by downregulation/absence of AR in certain subtypes that consequently do not respond to anti-androgen therapies. To highlight the significance of CRPC sub-classification, we reviewed the development and treatment of CRPC, AR downregulation in CRPC, and summarized recent reports on the prevalence of CRPC subtypes. Methods Using a medline-based literature search, we reviewed mechanisms of CRPC development, current treatment schemes, and assessed the prevalence of AR low/negative subtypes of CRPC. Additionally, we performed immunohistochemical staining on human CRPC specimens to quantify AR expression across CRPC subtypes. Results In the majority of cases, CRPC continues to rely on AR signaling, which can be augmented in castrate-conditions through a variety of mechanisms. However, recently low/negative AR expression patterns were identified in a significant proportion of patient samples from a multitude of independent studies. In these AR low/negative cases, we postulated that AR protein may be downregulated by (1) promoter methylation, (2) transcriptional regulation, (3) post-transcriptional regulation by microRNA or RNA-binding-proteins, or (4) post-translational ubiquitination-mediated degradation. Conclusions Here, we discussed mechanisms of CRPC development and summarized the overall prevalence of CRPC subtypes; interestingly, AR low/negative CRPC represented a considerable proportion of diagnoses. Because these subtypes cannot be effectively treated with AR-targeted therapeutics, a better understanding of AR low/negative subtypes could lead to better treatment strategies and increased survival.

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“…Higher testosterone levels are associated with smaller prostate size ( Xia et al, 2021 ), and younger age testosterone replacement therapy leads to prostate stabilization ( Zhang Q. et al, 2020 ). In prostate cancer patients, low serum testosterone has been found to be associated with androgen receptor expression ( Schatzl et al, 2002 ; Husain et al, 2016 ; Feng and He, 2019 ; Hashmi et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

Phua

2023

Front. Aging

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Aging-related hypoxia, oxidative stress, and inflammation pathophysiology are closely associated with human age-related carcinogenesis and chronic diseases. However, the connection between hypoxia and hormonal cell signaling pathways is unclear, but such human age-related comorbid diseases do coincide with the middle-aging period of declining sex hormonal signaling. This scoping review evaluates the relevant interdisciplinary evidence to assess the systems biology of function, regulation, and homeostasis in order to discern and decipher the etiology of the connection between hypoxia and hormonal signaling in human age-related comorbid diseases. The hypothesis charts the accumulating evidence to support the development of a hypoxic milieu and oxidative stress-inflammation pathophysiology in middle-aged individuals, as well as the induction of amyloidosis, autophagy, and epithelial-to-mesenchymal transition in aging-related degeneration. Taken together, this new approach and strategy can provide the clarity of concepts and patterns to determine the causes of declining vascularity hemodynamics (blood flow) and physiological oxygenation perfusion (oxygen bioavailability) in relation to oxygen homeostasis and vascularity that cause hypoxia (hypovascularity hypoxia). The middle-aging hypovascularity hypoxia hypothesis could provide the mechanistic interface connecting the endocrine, nitric oxide, and oxygen homeostasis signaling that is closely linked to the progressive conditions of degenerative hypertrophy, atrophy, fibrosis, and neoplasm. An in-depth understanding of these intrinsic biological processes of the developing middle-aged hypoxia could provide potential new strategies for time-dependent therapies in maintaining healthspan for healthy lifestyle aging, medical cost savings, and health system sustainability.

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Role of androgen receptor in prostatic neoplasia versus hyperplasia

Cited by 14 publications

References 1 publication

Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Development and prevalence of castration-resistant prostate cancer subtypes

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

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