17β-Hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer

Abstract

The 17b-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the local regulation of sex steroids. The 17HSD type 1 enzyme catalyses the interconversion of the weak oestrone (E1) to the more potent oestradiol (E2), whereas 17HSD type 2 catalyses the oxidation of E2 to E1. The aim of this study was to correlate the expression of these enzymes in the tumour with the recurrence-free survival of tamoxifen-treated breast cancer patients. We used real-time reverse transcriptase PCR to investigate the mRNA expression of 17HSD types 1 and 2 in tumour samples from 230 postmenopausal patients. For the patients with oestrogen receptor (ER)-positive breast cancer, we found a statistically significant positive correlation between recurrence-free survival and expression of 17HSD type 2 (P ¼ 0.026). We examined the ratio of 17HSD types 2 and 1, and ER-positive patients with low ratios showed a significantly higher rate of recurrence than those with higher ratios (P ¼ 0.0047). ER positive patients with high expression levels of 17HSD type 1 had a significantly higher risk for late relapse (P ¼ 0.0051). The expression of 17HSD types 1 and 2 in breast cancer differs from the expression of these enzymes in normal mammary gland, and this study indicates that the expression has prognostic significance in breast cancer.

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

“…In addition, expression of an androgen-induced gene 17bHSD2 may reflect intratumoral DHT actions in breast carcinoma more precisely than AR status. Gunnarsson et al (2005) reported a significant association between 17bHSD2 mRNA and better recurrence-free survival in the breast carcinoma. Therefore, 17bHSD2-positive breast carcinoma after a neoadjuvant aromatase inhibitor therapy possibly may grow more slowly by increased intratumoral DHT actions and/or further decreased estrogen actions by 17bHSD2 (Fig.…”

Progesterone and levonorgestrel regulate expression of 17βHSD-enzymes in progesterone receptor positive breast cancer cell line T47D

“…17βHSD5 converts androstendione to testosterone and oestrone to oestradiol. We have previously shown that 17βHSD1, 17βHSD2, 17βHSD5 and 17βHSD14 are important as prognostic and treatment predictive factors in breast cancer [10][11][12][13]. It has been shown that progestins influence the oestradiol and testosterone levels, and these effects have been presumed to be an effect caused by altered regulation of 17βHSD enzymes; however the contribution of separate family members of the 17βHSD-family has not been addressed [14][15][16][17][18][19].…”

The role of the heterocycle in bis(hydroxyphenyl)triazoles for inhibition of 17β-Hydroxysteroid Dehydrogenase (17β-HSD) type 1 and type 2

“…The potency of steroidal sex hormones like E2 is modulated by enzymes of the 17β-hydroxysteroid dehydrogenase (17β-HSD) family (Lukacik et al, 2006), especially 17β-HSD1 and 17β-HSD2, which catalyze the activation of E2 from estrone (E1) or the deactivation of E2 into E1, respectively (Chart 1). 17β-HSD1 is a cytosolic enzyme present in different organs like ovaries, placenta, breast, endometrium (Vihko et al, 2001) which is often overexpressed in breast cancer tissues (Suzuki et al, 2000;Gunnarsson et al, 2001;Miyoshi et al, 2001;Gunnarsson et al, 2005) and endometriosis (Šmuc et al, 2007). Consequently, selective inhibition of 17β-HSD1 is discussed to be a good strategy to reduce the intracellular E2 levels and regarded as a new therapeutic approach for the treatment of estrogen-dependent diseases.…”