SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer.
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.
Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. kclausen@wfubmc.edu
Kathryn A
KA
Clausen
Kimberly R
KR
Blish
Charles E
CE
Birse
Matthew A
MA
Triplette
Timothy E
TE
Kute
Gregory B
GB
Russell
Ralph B
RB
D'Agostino
Lance D
LD
Miller
Frank M
FM
Torti
Suzy V
SV
Torti
D048868:Adaptor Proteins, Signal Transducing; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; C480733:SOSTDC1 protein, human; D051785:Smad Proteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin