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01-10-2011 | Preclinical study

SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer

Authors: Kathryn A. Clausen, Kimberly R. Blish, Charles E. Birse, Matthew A. Triplette, Timothy E. Kute, Gregory B. Russell, Ralph B. D’Agostino Jr., Lance D. Miller, Frank M. Torti, Suzy V. Torti

Published in: Breast Cancer Research and Treatment | Issue 3/2011

Abstract

Sclerostin domain containing 1 (SOSTDC1) protein regulates processes from development to cancer by modulating activity of bone morphogenetic protein (BMP) and wingless/int (Wnt) signaling pathways. As dysregulation of both BMP and Wnt signaling has been observed in breast cancer, we investigated whether disruption of SOSTDC1 signaling occurs in breast cancer. SOSTDC1 mRNA expression levels in breast tissue were examined using a dot blot. Affymetrix microarray data on SOSTDC1 levels were correlated with breast cancer patient survival using Kaplan–Meier plots. Correlations between SOSTDC1 protein levels and clinical parameters were assessed by immunohistochemistry of a breast cancer tissue microarray. SOSTDC1 secretion and BMP and Wnt signaling were investigated using immunoblotting. We found that SOSTDC1 is expressed in normal breast tissue and this expression is reduced in breast cancer. High levels of SOSTDC1 mRNA correlated with increased patient survival; conversely, SOSTDC1 protein levels decreased as tumor size and disease stage increased. Treatment of breast cancer cells with recombinant SOSTDC1 or Wise, a SOSTDC1 orthologue, demonstrated that SOSTDC1 selectively blocks BMP-7-induced Smad phosphorylation without diminishing BMP-2 or Wnt3a-induced signaling. In conclusion, SOSTDC1 mRNA and protein are reduced in breast cancer. High SOSTDC1 mRNA levels correlate with increased distant metastasis-free survival in breast cancer patients. SOSTDC1 differentially affects Wnt3a, BMP-2, and BMP-7 signaling in breast cancer cells. These results identify SOSTDC1 as a clinically important extracellular regulator of multiple signaling pathways in breast cancer.

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American cancer society (2010) Cancer facts and figures 2010. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-and-figures-2010

Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Malin J, Mamounas EP, Rowden D, Solky AJ, Sowers MR, Stearns V, Winer EP, Somerfield MR, Griggs JJ (2010) American society of clinical oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. doi:10.1200/JCO.2009.26.3756

Dawood S, Merajver SD, Viens P, Vermeulen PB, Swain SM, Buchholz TA, Dirix LY, Levine PH, Lucci A, Krishnamurthy S, Robertson FM, Woodward WA, Yang WT, Ueno NT, Cristofanilli M (2010) International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol. doi:10.1093/annonc/mdq345

Ashok M, Griffin P, Halpern M (2010) Impact of clinical and non-clinical factors on the choice of her2 test for breast cancer. Cancer Invest. doi:10.3109/07357907.2010.496753

Bolos V, Blanco M, Medina V, Aparicio G, Diaz-Prado S, Grande E (2009) Notch signalling in cancer stem cells. Clin Transl Oncol 11(1):11–19PubMedCrossRef

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRef

Logan CY, Nusse R (2004) The wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810. doi:10.1146/annurev.cellbio.20.010403.113126 PubMedCrossRef

Rubin LL, de Sauvage FJ (2006) Targeting the hedgehog pathway in cancer. Nat Rev Drug Discov 5(12):1026–1033. doi:10.1038/nrd2086 PubMedCrossRef

Zardawi SJ, O’Toole SA, Sutherland RL, Musgrove EA (2009) Dysregulation of hedgehog, wnt and notch signalling pathways in breast cancer. Histol Histopathol 24(3):385–398PubMed

10.

Avsian-Kretchmer O, Hsueh AJ (2004) Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists. Mol Endocrinol 18(1):1–12. doi:10.1210/me.2003-0227 PubMedCrossRef

11.

Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos PM, Smith JC, Krumlauf R (2003) Wise, a context-dependent activator and inhibitor of wnt signalling. Development 130(18):4295–4305PubMedCrossRef

12.

Kassai Y, Munne P, Hotta Y, Penttila E, Kavanagh K, Ohbayashi N, Takada S, Thesleff I, Jernvall J, Itoh N (2005) Regulation of mammalian tooth cusp patterning by ectodin. Science 309(5743):2067–2070. doi:10.1126/science.1116848 PubMedCrossRef

13.

Beaudoin GM 3rd, Sisk JM, Coulombe PA, Thompson CC (2005) Hairless triggers reactivation of hair growth by promoting wnt signaling. Proc Natl Acad Sci USA 102(41):14653–14658. doi:10.1073/pnas.0507609102 PubMedCrossRef

14.

Simmons DG, Kennedy TG (2002) Uterine sensitization-associated gene-1: a novel gene induced within the rat endometrium at the time of uterine receptivity/sensitization for the decidual cell reaction. Biol Reprod 67(5):1638–1645PubMedCrossRef

15.

Yanagita M, Okuda T, Endo S, Tanaka M, Takahashi K, Sugiyama F, Kunita S, Takahashi S, Fukatsu A, Yanagisawa M, Kita T, Sakurai T (2006) Uterine sensitization-associated gene-1 (usag-1), a novel bmp antagonist expressed in the kidney, accelerates tubular injury. J Clin Invest 116(1):70–79. doi:10.1172/JCI25445 PubMedCrossRef

16.

Blish KR, Wang W, Willingham MC, Du W, Birse CE, Krishnan SR, Brown JC, Hawkins GA, Garvin AJ, D’Agostino RB Jr, Torti FM, Torti SV (2008) A human bone morphogenetic protein antagonist is down-regulated in renal cancer. Mol Biol Cell 19(2):457–464. doi:10.1091/mbc.E07-05-0433 PubMedCrossRef

17.

Ohshima J, Haruta M, Arai Y, Kasai F, Fujiwara Y, Ariga T, Okita H, Fukuzawa M, Hata J, Horie H, Kaneko Y (2009) Two candidate tumor suppressor genes, meox2 and sostdc1, identified in a 7p21 homozygous deletion region in a wilms tumor. Genes Chromosomes Cancer 48(12):1037–1050. doi:10.1002/gcc.20705 PubMedCrossRef

18.

Laurikkala J, Kassai Y, Pakkasjarvi L, Thesleff I, Itoh N (2003) Identification of a secreted bmp antagonist, ectodin, integrating bmp, fgf, and shh signals from the tooth enamel knot. Dev Biol 264(1):91–105PubMedCrossRef

19.

Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the sost gene in patients with van buchem disease. J Med Genet 39(2):91–97PubMedCrossRef

20.

Koenig BB, Cook JS, Wolsing DH, Ting J, Tiesman JP, Correa PE, Olson CA, Pecquet AL, Ventura F, Grant RA et al (1994) Characterization and cloning of a receptor for bmp-2 and bmp-4 from nih 3t3 cells. Mol Cell Biol 14(9):5961–5974PubMed

21.

ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K (1994) Identification of type i receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269(25):16985–16988PubMed

22.

Derynck R, Zhang Y, Feng XH (1998) Smads: transcriptional activators of tgf-beta responses. Cell 95(6):737–740PubMedCrossRef

23.

Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K (2002) Two major smad pathways in tgf-beta superfamily signalling. Genes Cells 7(12):1191–1204PubMedCrossRef

24.

Yanagita M, Oka M, Watabe T, Iguchi H, Niida A, Takahashi S, Akiyama T, Miyazono K, Yanagisawa M, Sakurai T (2004) Usag-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney. Biochem Biophys Res Commun 316(2):490–500. doi:10.1016/j.bbrc.2004.02.075 PubMedCrossRef

25.

Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480. doi:10.1016/j.cell.2006.10.018 PubMedCrossRef

26.

He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-myc as a target of the apc pathway. Science 281(5382):1509–1512PubMedCrossRef

27.

Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin d1 in colon carcinoma cells. Nature 398(6726):422–426. doi:10.1038/18884 PubMedCrossRef

28.

Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A (1999) The cyclin d1 gene is a target of the beta-catenin/lef-1 pathway. Proc Natl Acad Sci USA 96(10):5522–5527PubMedCrossRef

29.

Guidato S, Itasaki N (2007) Wise retained in the endoplasmic reticulum inhibits wnt signaling by reducing cell surface lrp6. Dev Biol 310(2):250–263. doi:10.1016/j.ydbio.2007.07.033 PubMedCrossRef

30.

Alarmo EL, Kuukasjarvi T, Karhu R, Kallioniemi A (2007) A comprehensive expression survey of bone morphogenetic proteins in breast cancer highlights the importance of bmp4 and bmp7. Breast Cancer Res Treat 103(2):239–246. doi:10.1007/s10549-006-9362-1 PubMedCrossRef

31.

Arnold SF, Tims E, McGrath BE (1999) Identification of bone morphogenetic proteins and their receptors in human breast cancer cell lines: importance of bmp2. Cytokine 11(12):1031–1037. doi:10.1006/cyto.1999.0508 PubMedCrossRef

32.

Clement JH, Raida M, Sanger J, Bicknell R, Liu J, Naumann A, Geyer A, Waldau A, Hortschansky P, Schmidt A, Hoffken K, Wolft S, Harris AL (2005) Bone morphogenetic protein 2 (bmp-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells. Int J Oncol 27(2):401–407PubMed

33.

Alarmo EL, Rauta J, Kauraniemi P, Karhu R, Kuukasjarvi T, Kallioniemi A (2006) Bone morphogenetic protein 7 is widely overexpressed in primary breast cancer. Genes Chromosomes Cancer 45(4):411–419. doi:10.1002/gcc.20307 PubMedCrossRef

34.

Howe LR, Brown AM (2004) Wnt signaling and breast cancer. Cancer Biol Ther 3(1):36–41PubMedCrossRef

35.

Brown AM (2001) Wnt signaling in breast cancer: have we come full circle? Breast Cancer Res 3(6):351–355PubMedCrossRef

36.

Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC (2000) Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin d1 expression and cancer progression. Proc Natl Acad Sci USA 97(8):4262–4266. doi:10.1073/pnas.060025397 PubMedCrossRef

37.

Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102(38):13550–13555. doi:10.1073/pnas.0506230102 PubMedCrossRef

38.

Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, Lindahl T, Pawitan Y, Hall P, Nordgren H, Wong JE, Liu ET, Bergh J, Kuznetsov VA, Miller LD (2006) Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res 66(21):10292–10301. doi:10.1158/0008-5472.CAN-05-4414 PubMedCrossRef

39.

Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, Ellis P, Harris A, Bergh J, Foekens JA, Klijn JG, Larsimont D, Buyse M, Bontempi G, Delorenzi M, Piccart MJ, Sotiriou C (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25(10):1239–1246. doi:10.1200/JCO.2006.07.1522 PubMedCrossRef

40.

Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, Liu ET, Miller L, Nordgren H, Ploner A, Sandelin K, Shaw PM, Smeds J, Skoog L, Wedren S, Bergh J (2005) Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res 7(6):R953–R964. doi:10.1186/bcr1325 PubMedCrossRef

41.

Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, Gillet C, Ellis P, Ryder K, Reid JF, Daidone MG, Pierotti MA, Berns EM, Jansen MP, Foekens JA, Delorenzi M, Bontempi G, Piccart MJ, Sotiriou C (2008) Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics 9:239. doi:10.1186/1471-2164-9-239 PubMedCrossRef

42.

Stackhouse BL, Williams H, Berry P, Russell G, Thompson P, Winter JL, Kute T (2005) Measurement of glut-1 expression using tissue microarrays to determine a race specific prognostic marker for breast cancer. Breast Cancer Res Treat 93(3):247–253. doi:10.1007/s10549-005-5158-y PubMedCrossRef

43.

Lehr HA, Mankoff DA, Corwin D, Santeusanio G, Gown AM (1997) Application of photoshop-based image analysis to quantification of hormone receptor expression in breast cancer. J Histochem Cytochem 45(11):1559–1565PubMedCrossRef

44.

Lintern KB, Guidato S, Rowe A, Saldanha JW, Itasaki N (2009) Characterization of wise protein and its molecular mechanism to interact with both wnt and bmp signals. J Biol Chem 284(34):23159–23168. doi:10.1074/jbc.M109.025478 PubMedCrossRef

45.

Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, Popescu NC, Hahn WC, Weinberg RA (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15(1):50–65PubMedCrossRef

46.

Knosp WM, Saneyoshi C, Shou S, Bachinger HP, Stadler HS (2007) Elucidation, quantitative refinement, and in vivo utilization of the hoxa13 DNA binding site. J Biol Chem 282(9):6843–6853. doi:10.1074/jbc.M610775200 PubMedCrossRef

47.

Yamamoto A, Nagano T, Takehara S, Hibi M, Aizawa S (2005) Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors, wnt and fgf. Cell 120(2):223–235. doi:10.1016/j.cell.2004.11.051 PubMedCrossRef

48.

Verras M, Papandreou I, Lim AL, Denko NC (2008) Tumor hypoxia blocks wnt processing and secretion through the induction of endoplasmic reticulum stress. Mol Cell Biol 28(23):7212–7224. doi:10.1128/MCB.00947-08 PubMedCrossRef

49.

Ye L, Lewis-Russell JM, Kyanaston HG, Jiang WG (2007) Bone morphogenetic proteins and their receptor signaling in prostate cancer. Histol Histopathol 22(10):1129–1147PubMed

50.

Ghosh-Choudhury N, Ghosh-Choudhury G, Celeste A, Ghosh PM, Moyer M, Abboud SL, Kreisberg J (2000) Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated mcf-7 human breast cancer cells. Biochim Biophys Acta 1497(2):186–196PubMedCrossRef

Title: SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer
Authors: Kathryn A. Clausen
Kimberly R. Blish
Charles E. Birse
Matthew A. Triplette
Timothy E. Kute
Gregory B. Russell
Ralph B. D’Agostino Jr.
Lance D. Miller
Frank M. Torti
Suzy V. Torti
Publication date: 01-10-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-1261-9

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