Expression of aromatase and 17β-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer

Song, Dong Eun; Liu, G.; Luu‐The, Van; Zhao, Dawei; Wang, L.; Zhang, H.; Xueling, G.; Li, S.; Désy, L.; Labrie, Fernand; Pelletier, Georges

doi:10.1016/j.jsbmb.2006.06.015

Cited by 58 publications

(53 citation statements)

References 33 publications

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“…A similar variation in results concerning 17HSD2 has been reported. The rate of mRNA-positive cases ranges from 14% to 25% (1, 2, 5) and protein expression from 0 to 61% (5,6,17,18). Reasons for the differences are not known.…”

Section: Discussionmentioning

confidence: 99%

Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients

Jansson¹,

Delander²,

Gunnarsson³

et al. 2009

Clinical Cancer Research

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Purpose: Estrogens have great significance in the development of breast cancer. After menopause, most estrogen biosynthesis is done in peripheral tissue, and the main enzymes involved in balancing the amount of estrone against estradiol are 17β-hydroxysteroid dehydrogenases (17HSD). The aim of this study was to investigate the prognostic and tamoxifen predictive values of 17HSD1 and 17HSD2 expression. Experimental Design: Tumors from low-risk breast cancer patients randomized to adjuvant tamoxifen therapy or no adjuvant treatment were analyzed with immunohistochemistry to investigate protein expression of 17HSD1 and 17HSD2 in 912 cases. All patients had lymph node-negative breast cancer and were postmenopausal at the time of diagnosis. Results: Low 17HSD1 expression was associated with significant benefit from tamoxifen treatment among patients with estrogen receptor (ER)-positive tumors (P < 0.001). For patients with a 17HSD1 score not exceeding that of 17HSD2, tamoxifen increased the rate of distant recurrence-free survival (hazard ratio, 0.37; 95% confidence interval, 0.23-0.60) and breast cancer-specific survival (hazard ratio, 0.30; 95% confidence interval, 0.16-0.54), whereas no apparent effect was observed when the 17HSD1 score was higher than that of 17HSD2. The interaction was significant for both distant recurrencefree survival (P = 0.036) and breast cancer-specific survival (P = 0.014). In the cohort of systemically untreated patients, no prognostic importance was observed. Conclusions: This is the first report that clearly distinguishes between the prognostic and predictive importance of 17HSD1 and 17HSD2 in ER-positive breast cancer treated with or without tamoxifen. Our data suggest that the 17HSD1/17HSD2 ratio might be useful as a predictive factor for tamoxifen treatment in ER-positive breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients

Jansson¹,

Delander²,

Gunnarsson³

et al. 2009

Clinical Cancer Research

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“…17h-HSD12 has also been shown in human breast cancer in two previous reports (9,10). Song and colleagues (9) showed that the expression of 17h-HSD12 in human breast carcinoma was significantly higher than nonmalignant breast tissue using immunohistochemical analysis.…”

Section: Introductionmentioning

confidence: 88%

17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis

Nagasaki

Suzuki²,

Miki³

et al. 2009

Cancer Research

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Abstract17B-Hydroxysteroid dehydrogenase type 12 (17B-HSD12) has been shown to be involved in elongation of very long chain fatty acid (VLCFA) as well as in biosynthesis of estradiol (E2). 17B-HSD12 expression was also reported in breast carcinomas but its functions have remained unknown. In this study, we examined the correlation between mRNA expression profiles determined by microarray analysis and tissue E2 concentrations obtained from 16 postmenopausal breast carcinoma cases. No significant correlations were detected between 17B-HSD12 expression and E2 concentration. We then immunolocalized this enzyme in 110 cases of invasive ductal carcinoma. 17B-HSD12 immunoreactivity in breast carcinoma cells was significantly associated with poor prognosis of the patients. We further examined the biological significance of 17B-HSD12 using cell-based studies. Small interfering RNA-mediated knockdown of 17B-HSD12 in SK-BR-3 (estrogen receptornegative breast carcinoma cell line) resulted in significant growth inhibition, which was recovered by the addition of VLCFAs such as arachidonic acid. The status of 17B-HSD12 immunoreactivity was also correlated with adverse clinical outcome in cyclooxygenase 2 (COX2)-positive breast cancer patients but not in COX2-negative patients. Therefore, these findings indicated that 17B-HSD12 was not necessarily related to intratumoral E2 biosynthesis, at least in human breast carcinoma, but was rather correlated with production of VLCFAs such as arachidonic acid, which may subsequently be metabolized to prostaglandins by COX2 and result in tumor progression of the patients. [Cancer Res 2009;69(4):1392-9]

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“…Some recent studies have suggested that it may also be important in the reduction of E 1 to form E 2 (Luu-The et al 2006, Blanchard & Luu-The 2007, although other studies have indicated that it does not efficiently catalyse this reaction (Day et al 2008), despite its up-regulation in the tumours of breast cancer patients (Song et al 2006). However, investigation of its expression in normal human tissues indicated that it is highly expressed in many active lipid-metabolising tissues, including liver, kidney, heart and skeletal muscle, as well as in placenta and testis, with additional expression in other steroidogenic tissues such as adrenal gland, ovary and prostate (Sakurai et al 2006).…”

Section: B-hsdsmentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

114

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

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Expression of aromatase and 17β-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer

Cited by 58 publications

References 33 publications

Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients

Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients

17β-Hydroxysteroid Dehydrogenase Type 12 in Human Breast Carcinoma: A Prognostic Factor via Potential Regulation of Fatty Acid Synthesis

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

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