The Role of Secreted Frizzled Related Protein 4 (sFRP-4) in Regulating Oestradiol-Induced Growth of the MCF-7 Breast Cancer Cell Line

• Sally McLaren

  School of Surgery and Pathology and Laboratory Medicine, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009

• Frank Arfuso

  School of Anatomy, Physiology and Human Biology, Faculty of Life and Physical Sciences, 35 Stirling Highway, Crawley, Perth, Western Australia 6009

• Nik Zeps

  School of Surgery and Pathology and Laboratory Medicine, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009

• Arun Dharmarajan

  School of Anatomy, Physiology and Human Biology, Faculty of Life and Physical Sciences, 35 Stirling Highway, Crawley, Perth, Western Australia 6009

 The Wnt signalling pathway is involved in regulating cellular proliferation and differentiation, and aberrant activation has been described in several cancers including breast. Oestradiol up regulates Wnt pathway gene expression, and thereby activates the Wnt signalling pathway. We used the oestrogen-responsive breast cancer cell line MCF-7 to examine the effects of secreted frizzled related protein 4 (sFRP-4) on oestradiol-induced growth, including gene expression of the Wnt signalling pathway genes Frizzled Receptor, Wnt-10b, and catenin. We demonstrate here that sFRP-4 inhibits oestradiol-induced cell growth in the MCF-7 cell line and also down regulates oestradiol-induced expression of selected Wnt signalling genes includingcatenin. We propose that sFRP-4 is a potent inhibitor of the Wnt signalling pathway and may negatively regulate oestradiol-mediated proliferation in human breast cancer cells.

Wolf V, Ke G, Dharmarajan AM, Bielke W, Artuso L, Saurer S, et al. DDC-4, an apoptosis-associated gene, is a secreted frizzled relative. FEBS Lett 1997; 417(3): 385-9. http://dx.doi.org/10.1016/S0014-5793(97)01324-0

Guo K, Wolf V, Dharmarajan AM, Feng Z, Bielke W, Saurer S, et al. Apoptosis-associated gene expression in the corpus luteum of the rat. Biol Reprod 1998; 58(3): 739-46. http://dx.doi.org/10.1095/biolreprod58.3.739

Rattner A, Sabido O, Massoubre C, Rascle F, Frey J. Characterization of human osteoblastic cells: influence of the culture conditions. In Vitro Cell Dev Biol Anim 1997; 33(10): 757-62. http://dx.doi.org/10.1007/s11626-997-0154-7

Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem 1999; 274(23): 16180-7. http://dx.doi.org/10.1074/jbc.274.23.16180

Abu-Jawdeh G, Comella N, Tomita Y, Brown LF, Tognazzi K, Sokol SY, et al. Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy. Lab Invest 1999; 79(4): 439-47.

Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D, et al. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res 2004; 10(2): 615-25. http://dx.doi.org/10.1158/1078-0432.CCR-0707-03

Saran U, Arfuso F, Zeps N, Dharmarajan A. Secreted frizzled-related protein 4 expression is positively associated with responsiveness to cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers. BMC Cell Biology 2012; 13: 25. http://dx.doi.org/10.1186/1471-2121-13-25

Jacob F, Ukegjini K, Nixdorf S, Ford CE, Olivier J, Caduff R, et al. Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients. PloS One 2012; 7(2): e31885. http://dx.doi.org/10.1371/journal.pone.0031885

Bui TD, Rankin J, Smith K, Huguet EL, Ruben S, Strachan T, et al. A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas. Oncogene 1997; 14(10): 1249-53. http://dx.doi.org/10.1038/sj.onc.1200936

Kirikoshi H, Katoh M. Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. Int J Oncol 2002; 21(4): 895-900.

Kirikoshi H, Katoh M. Expression and regulation of WNT10B in human cancer: up-regulation of WNT10B in MCF-7 cells by beta-estradiol and down-regulation of WNT10B in NT2 cells by retinoic acid. Int J Mol Med 2002; 10(4): 507-11.

Prall OW, Rogan EM, Sutherland RL. Estrogen regulation of cell cycle progression in breast cancer cells. J Steroid Biochem Mol Biol 1998; 65(1-6): 169-74.

Katoh M. Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta-estradiol in MCF-7 cells. Int J Oncol 2003; 22(1): 209-12.

Katoh M. Regulation of WNT3 and WNT3A mRNAs in human cancer cell lines NT2, MCF-7, and MKN45. Int J Oncol 2002; 20(2): 373-7.

Kirikoshi H, Sekihara H, Katoh M. Expression of WNT14 and WNT14B mRNAs in human cancer, up-regulation of WNT14 by IFNgamma and up-regulation of WNT14B by beta-estradiol. Int J Oncol 2001; 19(6): 1221-5.

Saitoh T, Katoh M. Expression and regulation of WNT5A and WNT5B in human cancer: up-regulation of WNT5A by TNFalpha in MKN45 cells and up-regulation of WNT5B by beta-estradiol in MCF-7 cells. Int J Mol Med 2002; 10(3): 345-9.

Saitoh T, Mine T, Katoh M. Expression and regulation of WNT8A and WNT8B mRNAs in human tumor cell lines: up-regulation of WNT8B mRNA by beta-estradiol in MCF-7 cells, and down-regulation of WNT8A and WNT8B mRNAs by retinoic acid in NT2 cells. Int J Oncol 2002; 20(5): 999-1003.

Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 1996; 86(3): 391-9. http://dx.doi.org/10.1016/S0092-8674(00)80112-9

Wong SC, Lo SF, Lee KC, Yam JW, Chan JK, Wendy Hsiao WL. Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. J Pathol 2002; 196(2): 145-53. http://dx.doi.org/10.1002/path.1035

Hsieh M, Mulders SM, Friis RR, Dharmarajan A, Richards JS. Expression and localization of secreted frizzled-related protein-4 in the rodent ovary: evidence for selective up-regulation in luteinized granulosa cells. Endocrinology 2003; 144(10): 4597-4606. http://dx.doi.org/10.1210/en.2003-0048

Ford CE, Jary E, Ma SS, Nixdorf S, Heinzelmann-Schwarz VA, Ward RL. The Wnt gatekeeper SFRP4 modulates EMT, cell migration and downstream Wnt signalling in serous ovarian cancer cells. PloS One 2013; 8(1): e54362. http://dx.doi.org/10.1371/journal.pone.0054362

Hou X, Tan Y, Li M, Dey SK, Das SK. Canonical Wnt signaling is critical to estrogen-mediated uterine growth. Molecular Endocrinology 2004; 18(12): 3035-49. http://dx.doi.org/10.1210/me.2004-0259

Drake JM, Friis RR, Dharmarajan AM. The role of sFRP4, a secreted frizzled-related protein, in ovulation. Apoptosis 2003; 8(4): 389-97. http://dx.doi.org/10.1023/A:1024181203729

He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, et al. Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells. Cancer Res 2005 1; 65(3): 743-8.

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