17β‐hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone‐dependent breast cancer

Abstract

Oestradiol (E2) stimulates the growth of hormone-dependent breast cancer. 17b-hydroxysteroid dehydrogenases (17b-HSDs) catalyse the pre-receptor activation/inactivation of hormones and other substrates. 17b-HSD1 converts oestrone (E1) to active E2, but it has recently been suggested that another 17b-HSD, 17b-HSD12, may be the major enzyme that catalyses this reaction in women. Here we demonstrate that it is 17b-HSD1 which is important for E2 production and report the inhibition of E1-stimulated breast tumor growth by STX1040, a non-oestrogenic selective inhibitor of 17b-HSD1, using a novel murine model. 17b-HSD1 and 17b-HSD12 mRNA and protein expression, and E2 production, were assayed in wild type breast cancer cell lines and in cells after siRNA and cDNA transfection. Although 17b-HSD12 was highly expressed in breast cancer cell lines, only 17b-HSD1 efficiently catalysed E2 formation. The effect of STX1040 on the proliferation of E1-stimulated T47D breast cancer cells was determined in vitro and in vivo. Cells inoculated into ovariectomised nude mice were stimulated using 0.05 or 0.1 lg E1 (s.c.) daily, and on day 35 the mice were dosed additionally with 20 mg/kg STX1040 s.c. daily for 28 days. STX1040 inhibited E1-stimulated proliferation of T47D cells in vitro and significantly decreased tumor volumes and plasma E2 levels in vivo. In conclusion, a model was developed to study the inhibition of the major oestrogenic 17b-HSD, 17b-HSD1, in breast cancer. Both E2 production and tumor growth were inhibited by STX1040, suggesting that 17b-HSD1 inhibitors such as STX1040 may provide a novel treatment for hormone-dependent breast cancer.

Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3

“…RT-PCR analysis of LNCaP mRNA indicated that the wild type cells from this laboratory has shown that it is unable to mediate this reaction (Day et al, 2008b). Instead it is thought to be involved in the metabolism of fatty acids (Moon & Horton, 2003).…”

“…At present, none of these inhibitors has reached clinical trial, and only recently has efficacy been demonstrated in vivo for the first of the enzymes, 17-HSD1, in models of breast cancer (Day et al, 2006b;Husen et al, 2006;Day et al, 2008b).…”

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review

“…The enzyme catalyses both oxidative (17-hydroxy to 17-keto) and reductive (17-keto to 17-hydroxy) 17b-HSD activity with a proper cofactor added in vitro. However, in cultured cells, the h17 -HSD1 has been shown to catalyse predominantly the reductive reaction [247]. Although h17 -HSD1 expression in various peripheral tissues is low, its catalytic efficacy is markedly higher than those measured for 17 -HSD7 and 17 -HSD12 [248,242], suggesting an important role for 17 -HSD1 in peripheral E2 formation.…”

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

“…5α-reductase inhibitors. [17][18][19][20] Although a number of steroidal and nonsteroidal inhibitors of 17β-HSD1 [21][22][23] are described and there is experimental evidence for the effectiveness of 17β-HSD1 inhibition against human tumor cell lines in vitro and in animal models, there is no inhibitor under clinical evaluation. Moreover, no proof of principle study in an animal disease model has been conducted for the indication endometriosis, although this is a widespread disease for which no adequate medical treatment is available.…”