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

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 17ß hydroxysteroid dehydrogenases (17ßHSD), 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(-7) and 10(-9)M to investigate influence on 17ßHSD1, 17ßHSD2 and 17ßHSD5 mRNA expression measured by real time PCR. The expression of 17ßHSD1 increased in progesterone and levonorgestrel treated T47D cells (48 h 10(-7)M P=0.002; P<0.001) and 17ßHSD5 increased after progesterone treatment (48 h 10(-7)M P=0.003), whereas the expression of 17ßHSD2 decreased after the (48 h 10(-7)M P=0.003; P<0.001). Similar, but less prominent effects were seen in MCF7 and ZR75-1. The progestin effects on 17ßHSD-expression were lost when T47D cells were co-treated with progestins and the progesterone receptor (PgR) inhibitor mifprestone. We show that both reductive (17ßHSD1 and 17ßHSD5) and oxidative (17ßHSD2) members of the 17ßHSD-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. 17ßHSD-enzymes are important players in the regulation of sex steroids locally in breast tumours and tumoural expression of various 17ßHSD-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 17ßHSD-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.