Role of estrogens in development of prostate cancer

Härkönen, Pirkko; Mäkelä, Sari

doi:10.1016/j.jsbmb.2004.10.016

Cited by 153 publications

(128 citation statements)

References 91 publications

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Section: Discussionmentioning

confidence: 99%

“…Whereas the physiological role of these receptors is not known, they may contribute to mediation of estrogen's role in prostate carcinogen-esis and progression of prostate cancer [40,41]. Thus, prolonged treatment of adult rodents with estrogens together with low-dose T leads to the development of epithelial metaplasia and adenocarcinoma of the prostate [40]. Also on the negative side, estrogens may actually facilitate the development of Alzheimer's disease and other dementias: for men ages 70−91, various dementias have been associated with high levels of endogenous estrogen, but not of T [42].…”

Section: Discussionmentioning

confidence: 99%

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Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17β-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11β-methyl-19-nortestosterone (11β-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) α and β in competitive binding assays (IC 50 's: 5−12 × 10 −9 M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E 2 ) (EC 50 's: 10 −12 to 10 −11 M). C19 androgens (T, 17α-methyltestosterone (17α-MT), androstenedione (AD), and 16α-hydroxyandrostenedione (16α-OHAD)), 19-norandrogens (DMA,, and 7α-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 μM with recombinant human aromatase for 10−180 min at 37 °C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16α-OHAD was linear for 40−60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11β-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11β position.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…3,25,26 The growth-inhibitory effects of endocrine therapies are associated with the status of steroid receptors, such as the androgen receptor (AR) and estrogen receptor (ER). 25,26 The emergence of techniques to clone the orphan nuclear receptors in the 1980s prompted to investigate physiological functions of the orphan nuclear receptors in the targeted organs. 12,13 Among the orphan nuclear receptors, ERRa, b and g, the three closely related members of the ERR family, all have functional links with the activities of the ERs.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

Fujimura

Takahashi

Urano

et al. 2007

Intl Journal of Cancer

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The nuclear receptor ERRα (estrogen‐related receptor α) is known to modulate the estrogen‐signaling pathway, but the biological significance of ERRα in the prostate remains unclear. We investigated the expression of ERRα in human prostate tissues and cancer cell lines to evaluate the potential roles of the receptor in prostate cancer (PC). Western blot analysis of ERRα was performed in three cell lines of human PC (LNCaP, DU145 and PC‐3). The expressions of ERRα in cancerous lesions (n = 106) and benign foci (n = 99) of 106 surgically obtained prostate specimens were evaluated by immunohistochemistry. The relationships between the ERRα expression and clinicopathological features were evaluated. Western blot analysis using the polyclonal anti‐ERRα antibody detected a 52 kD band in all three PC cell lines. Positive immunostaining of ERRα in the nuclei was found in 73 (69%) cancerous and 47 (47.5%) benign epithelium, whereas the stromal tissues were negative for ERRα. The mean immunoreactivity score (IR score) of the cancerous lesions (3.5 ± 2.6) was significantly higher than that of the benign foci (1.8 ± 2.1) (p < 0.0001). The IR score of the cancerous lesions significantly correlated with the Gleason score (p = 0.0135). Univariate and multivariate hazard analyses revealed significant correlations between elevated ERRα expression and poor cancer‐specific survival (p = 0.0141 and 0.0367, respectively). The enhanced expression of ERRα might play a role in the development of human PC and serve as a significant prognostic factor for the disease. © 2006 Wiley‐Liss, Inc.

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“…Increased levels of oestrogens, whether from environmental or developmental exposures, have long been linked to the development of prostate cancer 73,74 . Oestrogens affect the growth and development of the prostate, and this occurs through indirect routes on the hypothalamic-pituitary-gonadal axis through prolactin, and also by direct effects mediated by oestrogen receptor-α (ERα), which is expressed primarily in the stroma, and oestrogen receptor-β(ERβ), which is expressed primarily in the epithelium [73][74][75][76] . Oestrogens given to neonatal rodents result in an 'imprinted state' or 'developmental oestrogenization' in which there are developmental defects, including a reduction in prostatic growth.…”

Section: Oestrogensmentioning

confidence: 99%

Inflammation in prostate carcinogenesis

et al. 2007

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About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease. NIH Public Access Author ManuscriptNat Rev Cancer. Author manuscript; available in PMC 2013 January 23. $watermark-text $watermark-text $watermark-textProstate cancer is the most common non-cutaneous malignant neoplasm in men in Western countries, responsible for the deaths of approximately 30,000 men per year in the United States 1 . The number of afflicted men is increasing rapidly as the population of males over the age of 50 grows worldwide. Therefore, finding strategies for the prevention of prostate cancer is a crucial medical challenge. As men in South East Asian countries have a low incidence of prostate cancer that increases rapidly after immigration to the West, this disease is not an intrinsic feature of ageing. The pathogenesis of prostate cancer reflects both hereditary and environmental components. What are the environmental factors and genetic variations that have produced such an epidemic of prostate cancer? Approximately 20% of all human cancers in adults result from chronic inflammatory states and/or chronic inflammation 2-4 (BOX 1), which are triggered by infectious agents or exposure to other environmental factors, or by a combination thereof. There is also emerging evidence that inflammation is crucial for the aetiology of prostate cancer. This evidence stems from epidemiological, histopathological and molecular pathological studies. The objective of this Review is to take a multidisciplinary approach to present and analyse such studies. Because several reviews related to these topics have been published [5][6][7] , here we will focus on new findings and ideas with the purpose of sparking innovative areas of investigation that might ultimately lead to the prevention of prostate cancer. Enigmas in the aetiology of prostate cancerAs in other cancers, prostate cancer develops through the accumulation of somatic genetic and epigenetic changes, resulting in the inactivation of tumour-suppressor genes and caretaker genes, and the activation of oncogenes 8,9 (TABLE 1). There is also evidence for an underlying genetic instability that might facilitate tumour progression 10,11 . Although these genetic and epigenetic changes are crucial for our understanding of 'how' prostate cancer arises, another key remaining question is 'why'...

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Role of estrogens in development of prostate cancer

Cited by 153 publications

References 91 publications

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Increased expression of estrogen‐related receptor α (ERRα) is a negative prognostic predictor in human prostate cancer

Inflammation in prostate carcinogenesis

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