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

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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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Abbreviations

APC:

Adenomatous polyposis coli

ATCC:

American Type Culture Collection

AUS:

Antigen unmasking solution

bax:

Bcl-2-associated X protein

BMP:

Bone morphogenetic protein

CK1gamma:

Casein kinase 1 gamma

DAB:

Diaminobenzidine

DKK1:

Dickkopf-1

DMEM:

Dulbecco’s Modified Eagle’s Medium

DMFS:

Distant Metastasis-Free Survival

ER:

Endoplasmic reticulum

EsR:

Estrogen Receptor

FBS:

Fetal bovine serum

Fzd:

Frizzled

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GEO:

Gene Expression Omnibus

GSK-3:

Glycogen synthase kinase-3

HME:

Human mammary epithelial cells

HRP:

Horseradish peroxidase

hTERT:

Human telomerase

IgG:

Immunoglobulin G

kDa:

Kilodalton

LN:

Lymph node

LRP:

Low density lipoprotein receptor-related protein

MEGM:

Mammary epithelial cell growth media

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate buffered saline

PTEN:

Phosphatase and tensin homolog

PVDF:

Polyvinylidene fluoride

Rb:

Retinoblastoma protein

SDS:

Sodium dodecyl sulfate

SOSTDC1:

Sclerostin domain containing 1

SV40:

Simian virus 40

T:

Tamoxifen

TMA:

Tissue microarray

Wnt:

Wingless/int

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Acknowledgments

This research was supported in part by National Institute of Health Training Grant T32CA079448 (KAC), Department of Defense Breast Cancer Research Program under award number W81XWH-05-1-0287 (KRB), and by National Institute of Health grant R21 CA11918 (SVT). The authors also acknowledge the Ben Mynatt family for their generous support for this study. We thank Nobue Itasaki for kindly providing the Wise cDNA construct.

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Authors and Affiliations

  1. Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Kathryn A. Clausen, Matthew A. Triplette, Lance D. Miller & Frank M. Torti

  2. Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Kimberly R. Blish

  3. Celera, Alameda, CA, 94502, USA

    Charles E. Birse

  4. Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Timothy E. Kute

  5. Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Timothy E. Kute, Gregory B. Russell, Ralph B. D’Agostino Jr., Frank M. Torti & Suzy V. Torti

  6. Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Gregory B. Russell & Ralph B. D’Agostino Jr.

  7. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Suzy V. Torti

Authors
  1. Kathryn A. Clausen
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  2. Kimberly R. Blish
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  3. Charles E. Birse
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  8. Lance D. Miller
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  9. Frank M. Torti
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Correspondence to Kathryn A. Clausen.

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Supplementary material 1 (DOC 29 kb)

10549_2010_1261_MOESM2_ESM.tif

Fig. S1 SOSTDC1 does not inhibit BMP-2-induced Smad phosphorylation in breast cancer cells. MCF7 cells were treated for 4 h with BMP-2 (75 ng/ml) with or without Noggin or SOSTDC1 cotreatment (150 ng/ml). Cellular proteins were gel-resolved and immunoblotted to detect phosphoSmads 1/5/8. Equal protein loading was verified with the detection of GAPDH and non-phosphorylated Smads 1/5/8 (TIFF 65 kb)

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Clausen, K.A., Blish, K.R., Birse, C.E. et al. SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer. Breast Cancer Res Treat 129, 737–746 (2011). https://doi.org/10.1007/s10549-010-1261-9

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