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

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• 作者：Tove Sivik ; Agneta Jansson ; ^{agneta.jansson@liu.se}
• 关键词：Breast cancer ; Progestin ; Progesterone ; 17尾HSD1 ; 17尾HSD2
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：25 May, 2012
• 卷：422
• 期：1
• 页码：109-113
• 文件大小：486 K

摘要

The use of combined hormone replacement therapy (HRT) with oestrogens and progestins in postmenopausal women has been associated with an increased risk for developing breast cancer. The reasons are not fully understood, but influence of HRT on endogenous conversion of female sex hormones may be involved. The expression of 17尾 hydroxysteroid dehydrogenases (17尾HSD), which are enzymes catalysing the conversion between more or less potent oestrogens, may partly be regulated by progestins. The breast cancer cell lines T47D, MCF7 and ZR75-1 were treated with progesterone, medroxyprogesterone acetate (MPA) or levonorgestrel for 48 and 72 h at 10^鈭? and 10^鈭? M to investigate influence on 17尾HSD1, 17尾HSD2 and 17尾HSD5 mRNA expression measured by real time PCR. The expression of 17尾HSD1 increased in progesterone and levonorgestrel treated T47D cells (48 h 10^鈭? M P = 0.002; P < 0.001) and 17尾HSD5 increased after progesterone treatment (48 h 10^鈭? M P = 0.003), whereas the expression of 17尾HSD2 decreased after the (48 h 10^鈭? M P = 0.003; P < 0.001). Similar, but less prominent effects were seen in MCF7 and ZR75-1. The progestin effects on 17尾HSD-expression were lost when T47D cells were co-treated with progestins and the progesterone receptor (PgR) inhibitor mifprestone. We show that both reductive (17尾HSD1 and 17尾HSD5) and oxidative (17尾HSD2) members of the 17尾HSD-family are under control of progesterone and progestins in breast cancer cell lines. This is most clear in T47D cells which have high PgR expression. 17尾HSD-enzymes are important players in the regulation of sex steroids locally in breast tumours and tumoural expression of various 17尾HSD-enzymes have prognostic and treatment predictive relevance. We propose a mechanism for increased breast cancer risk after HRT in which hormone replacement affects the expression of 17尾HSD-enzymes, favouring the expression of reductive enzymes, which in turn could increase levels of bioactive and mitogenic estrogens in local tissue, e.g. breast tissue.