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

Abstract

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 beta hydroxysteroid dehydrogenases (17βHSD), which are enzymes catalysing the conversion between more or less potent oestrogens, may partly be regulated by progestins. The breast cancer cell lines T47D, MCF-7 and ZR75-1 were treated with progesterone, medroxyprogesterone acetate (MPA) or levonorgestrel for 48 and 72 hours at 10 -7 M and 10 -9 M to investigate influence on 17βHSD1, 17βHSD2 and 17βHSD5 mRNA expression measured by real time PCR. The expression of 17βHSD1 increased in progesterone and levonorgestrel treated T47D cells (48h 10 -7 M P=0.002; P<0.001) and 17βHSD5 increased after progesterone treatment (48 h 10 -7 M P=0.003), whereas the expression of 17βHSD2 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 17βHSD-expression were lost when T47D-cells were co-treated with progestins and the progesterone receptor (PgR) inhibitor mifprestone. We show that both reductive (17βHSD1 and 17βHSD5) and oxidative (17βHSD2) members of the 17βHSD-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. 17βHSD enzymes are important players in the regulation of sex steroids locally in breast tumours and tumoural expression of various 17βHSD-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 17βHSD-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.

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer

“…It has been reported that progestins, used as a treatment for endometriosis or included in hormone replacement therapy can influence the oxidative and reductive capacity of tissues, and medrogestone, 20-dihydro-dydrogesterone, and nomegestrol acetate all reduce HSD17B1 activity by 35-51% in cell lines tested [36, 55]. In the strongly progesterone receptor (PgR) positive breast cancer cell line T-47D, progesterone, levonorgestrel, and medroxyprogesterone acetate were shown to up-regulate HSD17B1 and HSD17B5 expression and down-regulate HSD17B2 expression, with smaller effects seen on HSD17B1 expression in the moderately positive MCF7 [79]. Recently the progestin Dienogest was shown to down-regulate both HSD17B1 and aromatase expression in endometriosis patients, if this is also applicable in breast cancer remains to be seen [80].…”

Electrochemical Magnetoimmunosensor for Progesterone Receptor Determination. Application to the Simultaneous Detection of Estrogen and Progesterone Breast‐cancer Related Receptors in Raw Cell Lysates.

“…It is also important to notice that the MCF‐7 cell line used as positive control shows, in fact, an intermediate PR expression level in comparison with other human breast cancer cell lines such as T47D, which presents an approximately 20‐fold higher PR mRNA level . Therefore, the magnetoimmunosensor ability to clearly differentiate cells expressing an intermediate PR level highlights the potentiality of the developed methodology.…”

Characterization and in vitro Evaluation of a New Levonorgestrel Silver Liposomes

“…Some studies suggest that systemic progesterone treatment contributes to increased expression levels of reductive enzymes compared to oxidative ones, which results in a possible increase of estrogen hormones and thus increases the proliferation of breast epithelial cells. [11,12] In order to assess the cytotoxic impact of levonorgestrel silver nanoparticles and their liposomal systems on breast epithelial cells -MCF 10A, there were selected two concentrations 0.1 μM and 1 μM, respectively for 24 h. The data obtained revealed that at 0.1 μM no significant influence on cell viability was noted for 24 h (data not shown). At a concentration of 1 µM, there was a slight decrease in cell viability after treatment with Ag_NPs (viability ~93%), Lng_Ag_NPs (viability ~94%) and Lip_Ag_NPs (viability ~94%) (Fig.…”