SOSTDC1: A BMP/Wnt Dual Antagonist in Breast and Renal Cancers

ABSTRACT Blish, Kimberly Rose SOSTDC1: A BMP/WNT DUAL ANTAGONIST IN BREAST AND RENAL CANCERS Dissertation under the direction of Suzy V. Torti, Ph.D., Associate Professor of Biochemistry The bone morphogenetic protein (BMP) pathway and the Wnt pathway are signaling networks associated with carcinogenesis. BMPs and Wnts are powerful morphogens and downstream signaling affects critical cell functions such as proliferation, differentiation, and viability. Proper regulation of these pathways is essential to prevent of transformation in normal cells. SOSTDC1 (SclerOSTin Domain-Containing-1) is an inhibitor of BMP/Wnt signaling in mouse disease models; however, little is known about the expression or actions of SOSTDC1 in human tissue. This work expands upon the observation that SOSTDC1 downregulation occurs in 85-90% of breast and kidney tumors. It was hypothesized that extracellular BMP regulation by SOSTDC1 is protective against cancer; therefore, loss of SOSTDC1 may lead to tumorigenesis initiation or progression. This was investigated through studies of the SOSTDC1 gene locus on chromosome 7, examination of the expression and actions of SOSTDC1 in cell culture models, and evaluation of SOSTDC1 within clinical samples. Human SOSTDC1 protein is expressed in normal kidney and breast tissue. Mature SOSTDC1 is secreted from normal kidney and breast cells but is not detectable from breast cancer cell lines. The distinction is relevant as SOSTDC1 in the extracellular space effectively antagonizes BMP signaling in breast and kidney cancer cells. Additionally, SOSTDC1 antagonizes Wnt signaling in cell models of kidney cancer. When expression of SOSTDC1 is restored to kidney or breast cancer cell models, striking inhibition of culture proliferation is achieved and cannot be rescued with BMP treatment alone. This suggests that therapeutic potential of exogenous SOSTDC1 may come through concurrent dual BMP and Wnt pathway inhibition. Genetic studies revealed loss-of-heterozygosity (LOH) at the SOSTDC1 locus in 10% of renal carcinomas and pediatric Wilms Tumors. Searches for a putative Wilms Tumor suppressor at this locus are ongoing and SOSTDC1 may be a viable candidate. Evaluation of SOSTDC1 protein in clinical renal cell carcinomas and breast tumors reveals a significant loss of protein in renal clear cell carcinomas and breast tumors of advanced stage. Loss of SOSTDC1 may be a biomarker for more advanced breast disease.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2009

Author dc:creator

• Blish, Kimberly

• molecular biology

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10339/14815

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/14815