ECE2017 Oral Communications Cardiovascular endocrinology (1) (5 abstracts)
Estrogens enhance gonadectomy-induced adrenocortical tumor progression in mice
Marcin Chrusciel 1, , Milena Doroszko 1 , Meike Jakobi 1 , Michal Brouze 1 , Donata Ponikwicka-Tyszko 3 , Piotr Bernaczyk 4 , Slawomir Anisimowicz 5 , Slawomir Wolczynski 2, , Jorma Toppari 1, , Ilpo Huhtaniemi 1, & Nafis Rahman 1,
1Department of Physiology, University of Turku, Turku, Finland; 2Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland; 3Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland; 4Department of Pathology, Medical University of Bialystok, Bialystok, Poland; 5Center of Gynecology and Reproductive Endocrinology Artemida, Bialystok, Poland; 6Department of Pediatrics, Turku University Hospital, Turku, Finland; 7Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.
Prepubertally gonadectomized (GDX) wild-type DBA/2J mice develop adrenocortical neoplasms presenting with small spindle-shaped non steroidogenic A-cells and large lipid-laden, steroidogenic and mitotically active B-cells. Neoplastic B-cells overexpress estrogen receptor α (ERα, Ers1) and β (ERβ, Ers2), aromatase (CYP19a1) and produce sex-steroids, resembling gonadal rest tissue. To test the role of estrogen-ER system in adrenocortical tumor progression, GDX 12 months-old DBA/2J females were treated with selective estrogen receptor modulator tamoxifen (TMX, 0.4 mg/kg/24 h) and aromatase inhibitor letrozole (LET, 2 mg/kg/24 h) for 21 days. Both TMX and LET treatments significantly reduced the adrenal weights, with stronger effect of the latter. Both treatments decreased the expression of proliferation marker MKI67 and induced apoptosis predominantly in the tumorous B-cells. TMX and LET treatments decreased plasma estradiol (E2) levels significantly decreasing sensitivity of the negative feedback on luteinizing hormone (LH) secretion. Gene expression profiling showed that TMX and LET downregulated gonadal-like markers Ers2, LH receptor (Lhcgr) and transcription factor Gata4, but upregulated a negative regulator of steroidogenesis Nr0b1. Additionally, LET significantly decreased expression of Esr1, Cyp19a1 and Cyp17a1. Control GDX mouse uteri displayed endometrial hyperplasia without cellular atypia. TMX- and LET-treated mice uteri were significantly smaller and showed cystically dilated endometrial glands and signs of mild chronic inflammation. In summary, we showed that adrenal estrogens promote progression of GDX-induced adrenocortical tumors. Our findings also support the rationale for TMX- and LET-based therapeutic strategies in treating ERs-positive/estrogen responsive adrenocortical carcinomas in human.
Volume 49
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Endocrine Abstracts
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