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

Abstract

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.

Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer

“…Procedures for immunochemical staining of S6K2 as well as Cyclin D1, and evaluation of antibody specificity using immunoblotting are presented in detail in Supplementary Methods. Preparation of breast cancer tissue microarrays (TMA) and evaluation of ER, progesterone receptor (PgR) and HER2 protein expression have been described previously [31].…”

WW Domain-Containing Oxidoreductase is a Potential Receptor for Sex Steroid Hormones

“…Estrogen provides a proliferative effect in majority of ERpositive breast cancer cells. Enzymes responsible for metabolizing steroid hormones are aromatase, estrone sulfatases, and 17 -hydroxysteroid dehydrogenases (17 -HSDs) (Jansson, 2009;Aka et al, 2009). These enzymes are present in breast cancer tissues (Miki et al, 2009).…”

“…Caenorhabditis elegans LET-767 is known to metabolize androgens and estrogens, and the gene appears to share a common ancestor with human types 17 -HSD3 and HSD12 (Desnoyers et al, 2007). High levels of expression of 17 -HSD1 have been shown to be associated with poor prognosis in breast cancer and late relapse among patients with ER-positive breast tumors (Sasaki et al, 2010;Jansson et al, 2009). In contrast, significant downregulation of 17 -HSD2 is also correlated with decreased survival in ER-positive breast cancer (Sasaki et al, 2010;Jansson et al, 2009).…”

“…High levels of expression of 17 -HSD1 have been shown to be associated with poor prognosis in breast cancer and late relapse among patients with ER-positive breast tumors (Sasaki et al, 2010;Jansson et al, 2009). In contrast, significant downregulation of 17 -HSD2 is also correlated with decreased survival in ER-positive breast cancer (Sasaki et al, 2010;Jansson et al, 2009). Similarly, significantly reduced expression of 17 -HSD14 mRNA in breast cancer is also associated with decreased survival (Jansson et al, 2009).…”

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].…”