G4 Monograph dissertation
Hydroxysteroid (17beta) dehydrogenase 1 expression enhances estrogen action and serves as a potential drug target for reducing estrogen signaling in the uterus and mammary glands
Authors: Järvensivu Päivi
Publisher: Turun yliopisto
Publishing place: Turku
Publication year: 2018
Journal name in sourceTurun yliopiston julkaisuja. Sarja D. Medica-Odontologica
Issue: 1333
ISBN: 978-951-29-7114-5
eISBN: 978-951-29-7115-2
Web address : http://urn.fi/URN:ISBN:978-951-29-7115-2
Self-archived copy’s web address: http://urn.fi/URN:ISBN:978-951-29-7115-2
Abstract
Hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) is a steroidmetabolizing enzyme with a preface for converting the low active estrogen estrone (E1) to highly active estradiol (E2). Accordingly, HSD17B1 is expressed particularly in E2-producing tissues such as the human placenta and ovaries. Moreover, HSD17B1 is expressed in peripheral estrogen target tissues such as the breast and uterus, where it controls local intratissue E2 concentration. Exposure to elevated concentrations of estrogens is associated with increased risk of several diseases, including breast cancer, which is the most common cancer in women worldwide. To investigate the significance of HSD17B1 in steroid production in vivo and in estrogen-dependent diseases, transgenic mice universally expressing human HSD17B1 enzyme (HSD17B1TG mice) were used. These mice showed increased peripheral conversion of E1 to E2 in a variety of tissues, including the uterus and mammary glands. Female HSD17B1TG mice developed endometrial
hyperplasia, a precursor to endometrial carcinoma. The hyperplasia was reversed by ovulation induction, while initially the HSD17B1TG females failed to ovulate. Treatment with an HSD17B1 inhibitor also partly reversed the hyperplastic
morphology. The HSD17B1TG females developed mammary cancer at older age. Mammary gland epithelial restricted HSD17B1 expression formed mammary lesions with a disrupted myoepithelial cell layer and inflammatory cell infiltration that was reduced by blocking estrogen receptor signaling with an antiestrogen, ICI 182, 780. The HSD17B1TG mice were also successfully used as a preclinical model for screening the efficacy of HSD17B1 inhibitors in vivo by crossing HSD17B1TG mice with estrogen reporter mice (ERELuc mice). In these bi-TG mice, both an immature uterus growth response and estrogen receptor activity were used as readouts, and both were reduced by HSD17B1 inhibitor treatment. These studies elucidate the potential of HSD17B1 enzyme to enhance the action of E1 in peripheral tissues, thus, indicating that inhibition of HSD17B1 is a plausible approach to treating estrogen-dependent diseases.
Hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) is a steroidmetabolizing enzyme with a preface for converting the low active estrogen estrone (E1) to highly active estradiol (E2). Accordingly, HSD17B1 is expressed particularly in E2-producing tissues such as the human placenta and ovaries. Moreover, HSD17B1 is expressed in peripheral estrogen target tissues such as the breast and uterus, where it controls local intratissue E2 concentration. Exposure to elevated concentrations of estrogens is associated with increased risk of several diseases, including breast cancer, which is the most common cancer in women worldwide. To investigate the significance of HSD17B1 in steroid production in vivo and in estrogen-dependent diseases, transgenic mice universally expressing human HSD17B1 enzyme (HSD17B1TG mice) were used. These mice showed increased peripheral conversion of E1 to E2 in a variety of tissues, including the uterus and mammary glands. Female HSD17B1TG mice developed endometrial
hyperplasia, a precursor to endometrial carcinoma. The hyperplasia was reversed by ovulation induction, while initially the HSD17B1TG females failed to ovulate. Treatment with an HSD17B1 inhibitor also partly reversed the hyperplastic
morphology. The HSD17B1TG females developed mammary cancer at older age. Mammary gland epithelial restricted HSD17B1 expression formed mammary lesions with a disrupted myoepithelial cell layer and inflammatory cell infiltration that was reduced by blocking estrogen receptor signaling with an antiestrogen, ICI 182, 780. The HSD17B1TG mice were also successfully used as a preclinical model for screening the efficacy of HSD17B1 inhibitors in vivo by crossing HSD17B1TG mice with estrogen reporter mice (ERELuc mice). In these bi-TG mice, both an immature uterus growth response and estrogen receptor activity were used as readouts, and both were reduced by HSD17B1 inhibitor treatment. These studies elucidate the potential of HSD17B1 enzyme to enhance the action of E1 in peripheral tissues, thus, indicating that inhibition of HSD17B1 is a plausible approach to treating estrogen-dependent diseases.
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