SiRNA-based Breast Cancer Therapy by Suppressing 17β-hydroxysteroid Dehydrogenase Type 1 in an Optimized Xenograft Cell and Molecular Biology Model in Vivo

Overview

Journal Drug Des Devel Ther

Specialty Pharmacology

Date 2019 Mar 14

PMID 30863015

Citations 2

Authors

Fang Li

Zhihan Zhu

Man Xue

Wanhong He

Ting Zhang

Linglin Feng

Shengxiang Lin

Affiliations

Soon will be listed here.

Abstract

Purpose: Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17β-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity. Application of 17β-HSD1-siRNA in vivo is limited by the establishment of an animal model, as well as the potential nuclease activity in vivo. We tried to reveal the in vivo potential of 17β-HSD1-siRNA-based breast cancer therapy.

Materials And Methods: To establish a competent animal model, daily subcutaneous injection of an estrone micellar aqueous solution was adopted to provide the substrate for estradiol biosynthesis. The effects of three different doses of estrone (0.1, 0.5, and 2.5 µg/kg/day) on tumor growth in T47D-17β-HSD1-inoculated group were investigated and compared with the animals inoculated with wild type T47D cells. To solve in vivo delivery problem of siRNA, "17β-HSD1-siRNA/LPD", a PEGylated and modified liposome-polycation-DNA nanoparticle containing 17β-HSD1-siRNA was prepared by the thin film hydration method and postinsertion technology. Finally, "17β-HSD1-siRNA/LPD" was tested in the optimized model. Tumor growth and 17β-HSD1 expression were assessed.

Results: Comparison with the untreated group revealed significant suppression of tumor growth in "17β-HSD1-siRNA/LPD"-treated group when HSD17B1 gene expression was knocked down.

Conclusion: These findings showed promising in vivo assessments of 17β-HSD1-siRNA candidates. This is the first report of an in vivo application of siRNA for steroid-converting enzymes in a nude mouse model.

Citing Articles

Targeting the formation of estrogens for treatment of hormone dependent diseases-current status.

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Small interfering RNA for cancer treatment: overcoming hurdles in delivery.

Charbe N, Amnerkar N, Ramesh B, Tambuwala M, Bakshi H, Aljabali A Acta Pharm Sin B. 2020; 10(11):2075-2109.

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References

Perks C, Newcomb P, Norman M, Holly J . Effect of insulin-like growth factor binding protein-1 on integrin signalling and the induction of apoptosis in human breast cancer cells. J Mol Endocrinol. 1999; 22(2):141-50. DOI: 10.1677/jme.0.0220141. View

Qiu W, Campbell R, Gangloff A, Dupuis P, Boivin R, Tremblay M . A concerted, rational design of type 1 17beta-hydroxysteroid dehydrogenase inhibitors: estradiol-adenosine hybrids with high affinity. FASEB J. 2002; 16(13):1829-31. DOI: 10.1096/fj.02-0026fje. View

Gangloff A, Shi R, Nahoum V, Lin S . Pseudo-symmetry of C19 steroids, alternative binding orientations, and multispecificity in human estrogenic 17beta-hydroxysteroid dehydrogenase. FASEB J. 2002; 17(2):274-6. DOI: 10.1096/fj.02-0397fje. View

Gravekamp C, Sypniewska R, Gauntt S, Tarango M, Price P, Reddick R . Behavior of metastatic and nonmetastatic breast tumors in old mice. Exp Biol Med (Maywood). 2004; 229(7):665-75. DOI: 10.1177/153537020422900711. View

Husen B, Huhtinen K, Poutanen M, Kangas L, Messinger J, Thole H . Evaluation of inhibitors for 17beta-hydroxysteroid dehydrogenase type 1 in vivo in immunodeficient mice inoculated with MCF-7 cells stably expressing the recombinant human enzyme. Mol Cell Endocrinol. 2006; 248(1-2):109-13. DOI: 10.1016/j.mce.2005.11.042. View

Lukacik P, Kavanagh K, Oppermann U . Structure and function of human 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol. 2006; 248(1-2):61-71. DOI: 10.1016/j.mce.2005.12.007. View

Irahara N, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S . Quantitative analysis of aromatase, sulfatase and 17beta-HSD(1) mRNA expression in soft tissue metastases of breast cancer. Cancer Lett. 2006; 243(1):23-31. DOI: 10.1016/j.canlet.2005.11.010. View

Husen B, Huhtinen K, Saloniemi T, Messinger J, Thole H, Poutanen M . Human hydroxysteroid (17-beta) dehydrogenase 1 expression enhances estrogen sensitivity of MCF-7 breast cancer cell xenografts. Endocrinology. 2006; 147(11):5333-9. DOI: 10.1210/en.2006-0778. View

Poutanen M, Moncharmont B, Vihko R . 17 beta-hydroxysteroid dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin. Cancer Res. 1992; 52(2):290-4. View

10.

Day J, Foster P, Tutill H, Parsons M, Newman S, Chander S . 17beta-hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone-dependent breast cancer. Int J Cancer. 2008; 122(9):1931-40. DOI: 10.1002/ijc.23350. View

11.

Brozic P, Lanisnik Risner T, Gobec S . Inhibitors of 17beta-hydroxysteroid dehydrogenase type 1. Curr Med Chem. 2008; 15(2):137-50. DOI: 10.2174/092986708783330629. View

12.

Laplante Y, Rancourt C, Poirier D . Relative involvement of three 17beta-hydroxysteroid dehydrogenases (types 1, 7 and 12) in the formation of estradiol in various breast cancer cell lines using selective inhibitors. Mol Cell Endocrinol. 2008; 301(1-2):146-53. DOI: 10.1016/j.mce.2008.08.026. View

13.

Mazumdar M, Fournier D, Zhu D, Cadot C, Poirier D, Lin S . Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy. Biochem J. 2009; 424(3):357-66. DOI: 10.1042/BJ20091020. View

14.

Chen Y, Wu J, Huang L . Nanoparticles targeted with NGR motif deliver c-myc siRNA and doxorubicin for anticancer therapy. Mol Ther. 2010; 18(4):828-34. PMC: 2862540. DOI: 10.1038/mt.2009.291. View

15.

Aka J, Mazumdar M, Chen C, Poirier D, Lin S . 17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production. Mol Endocrinol. 2010; 24(4):832-45. PMC: 5417535. DOI: 10.1210/me.2009-0468. View

16.

Marchais-Oberwinkler S, Henn C, Moller G, Klein T, Negri M, Oster A . 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development. J Steroid Biochem Mol Biol. 2011; 125(1-2):66-82. DOI: 10.1016/j.jsbmb.2010.12.013. View

17.

Cariati M, Marlow R, Dontu G . Xenotransplantation of breast cancers. Methods Mol Biol. 2011; 731:471-82. DOI: 10.1007/978-1-61779-080-5_38. View

18.

Zhang C, Chen J, Yin D, Lin S . The contribution of 17beta-hydroxysteroid dehydrogenase type 1 to the estradiol-estrone ratio in estrogen-sensitive breast cancer cells. PLoS One. 2012; 7(1):e29835. PMC: 3253791. DOI: 10.1371/journal.pone.0029835. View

19.

Aka J, Zerradi M, Houle F, Huot J, Lin S . 17beta-hydroxysteroid dehydrogenase type 1 modulates breast cancer protein profile and impacts cell migration. Breast Cancer Res. 2012; 14(3):R92. PMC: 3446355. DOI: 10.1186/bcr3207. View

20.

Goldberg M . siRNA delivery for the treatment of ovarian cancer. Methods. 2013; 63(2):95-100. DOI: 10.1016/j.ymeth.2013.01.007. View