Abstract 2286: Medroxyprogesterone acetate induces expression of 17βHSD1 and 17βHSD5 in the progesterone receptor positive breast cancer cell lines T47D and MCF7

Abstract

Abstract Despite the fact that the ovaries stop to produce oestrogens at menopause, high levels can be detected locally in breast tumours. There are several enzymes responsible for the local production of sex steroids such as aromatase, and the 17 beta hyroxysteroid dehydrogenase (17βHSD) family has also proven to have a significant importance in breast cancer. 17βHSD1 converts estrone to estradiol, 17βHSD2 estradiol to estrone, 17βHSD5 androstendione to testosterone and in the next step aromatase is responsible for formation of testosterone to estradiol, the function of 17βHSD14 is still not clear. The regulation of 17βHSDs needs further investigation. In several studies combined hormone replacement therapy (estrogens and progestins) has shown an increased risk to develop invasive breast cancer, compared to women treated with only estrogens. It is plausible that progestins influence the expression of members in the 17βHSD-family. Previous studies investigating the role of progestins on steroid conversion have focused on measuring steroidal levels and have not investigated changes in expression levels of enzymes responsible for this conversion. The aim of this study was to treat breast cancer cell lines with progesterone and progestins to detect possible influence on 17βHSD1, 17βHSD2, 17βHSD5 and 17βHSD14 mRNA expression. We further investigated conversion of androstendione in cultured media. The breast cancer cell lines T47D, MCF7 and ZR75-1, choosen for their different endogenous expression of progesterone receptor (PgR) were exposed for progesterone, medroxyprogesterone acetate (MPA) or levenogestrel for 48 and 72 hours at 10-7 and 10-9 M. The mRNA expression of 17βHSD1, 17βHSD2, 17βHSD5 and 17βHSD14 were measured by real time PCR using assay on demand and ACTH as endogenous control. Conversion of H3 labelled androstendione was investigated using HPLC coupled radio detector. We found that mRNA expression of 17βHSD1 increased significantly after 48 h in MPA treated T47D (10-9 M p=0.03) and MCF7 cells (10-7 p=0.001; 10-9 p=0.004). Further, mRNA expression of 17βHSD5 increased after 48 h in MPA treated T47D (10-7 M p=0.0006; 10-9 M p=0.04) and MCF7 cells (10−9 M p=0.005). No significant differences were found in cells treatment with levonogestrel or progesterone. We did neither find any differences in the mRNA expression levels of 17βHSD2 nor 17βHSD14. In the ZR75-1 cell line no significant changes were detected. We have preliminary results indicating that androstendione is converted in T47D cells treated with MPA. In conclusion, we show that reductive members of the 17βHSD-family increase (17βHSD1 and 17βHSD5) in breast cancer cells with high PgR expression levels. Our results may indicate that 17βHSD5 can be involved in the high risk for breast cancer assessed with hormone replacement treatment using combined estrogen and progestin in post menopausal women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2286. doi:10.1158/1538-7445.AM2011-2286