Dataset Information

Androgens and prostate disease.

ABSTRACT: A growing body of literature has established the anabolic benefi ts of testosterone (T) therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently fi nd a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5?-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease.

SUBMITTER: Cooper LA

PROVIDER: S-EPMC3955334 | biostudies-other | 2014 Mar-Apr

REPOSITORIES: biostudies-other

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Androgens and prostate disease.

Cooper Lori A LA Page Stephanie T ST

Asian journal of andrology 20140301 2

A growing body of literature has established the anabolic benefi ts of testosterone (T) therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease ha ...[more]

PMID: 24407178

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Project description:BackgroundDisruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer.MethodsTo examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days.ResultsCell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner.ConclusionsOur findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.

Dataset Information

Androgens and prostate disease.

Publications

Androgens and prostate disease.

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