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Synergistic control of sex hormones by 17?-HSD type 7: a novel target for estrogen-dependent breast cancer.

ABSTRACT: 17?-hydroxysteroid dehydrogenase (17?-HSD) type 1 is known as a critical target to block the final step of estrogen production in estrogen-dependent breast cancer. Recent confirmation of the role of dyhydroxytestosterone (DHT) in counteracting estrogen-induced cell growth prompted us to study the reductive 17?-HSD type 7 (17?-HSD7), which activates estrone while markedly inactivating DHT. The role of DHT in breast cancer cell proliferation is demonstrated by its independent suppression of cell growth in the presence of a physiological concentration of estradiol (E2). Moreover, an integral analysis of a large number of clinical samples in Oncomine datasets demonstrated the overexpression of 17?-HSD7 in breast carcinoma. Inhibition of 17?-HSD7 in breast cancer cells resulted in a lower level of E2 and a higher level of DHT, successively induced regulation of cyclinD1, p21, Bcl-2, and Bik, consequently arrested cell cycle in the G(0)/G(1) phase, and triggered apoptosis and auto-downregulation feedback of the enzyme. Such inhibition led to significant shrinkage of xenograft tumors with decreased cancer cell density and reduced 17?-HSD7 expression. Decreased plasma E2 and elevated plasma DHT levels were also found. Thus, the dual functional 17?-HSD7 is proposed as a novel target for estrogen-dependent breast cancer by regulating the balance of E2 and DHT. This demonstrates a conceptual advance on the general belief that the major role of this enzyme is in cholesterol metabolism.

SUBMITTER: Wang X

PROVIDER: S-EPMC4664117 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Synergistic control of sex hormones by 17β-HSD type 7: a novel target for estrogen-dependent breast cancer.

Wang Xiaoqiang X Gérard Catherine C Thériault Jean-François JF Poirier Donald D Doillon Charles J CJ Lin Sheng-Xiang SX

Journal of molecular cell biology 20150512 6

17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 is known as a critical target to block the final step of estrogen production in estrogen-dependent breast cancer. Recent confirmation of the role of dyhydroxytestosterone (DHT) in counteracting estrogen-induced cell growth prompted us to study the reductive 17β-HSD type 7 (17β-HSD7), which activates estrone while markedly inactivating DHT. The role of DHT in breast cancer cell proliferation is demonstrated by its independent suppression of cell g ...[more]

PMID: 25966904

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Project description:INTRODUCTION:Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-? (ER?)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. METHODS:The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ER?-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ER?-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ER?-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ER?-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. RESULTS:In eight of nine ER?-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ER?-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (?10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. CONCLUSION:Given the established role for IL-6 in ER?-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer.

Dataset Information

Synergistic control of sex hormones by 17?-HSD type 7: a novel target for estrogen-dependent breast cancer.

Publications

Synergistic control of sex hormones by 17β-HSD type 7: a novel target for estrogen-dependent breast cancer.

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