Bone metastasis is the major cause of morbidity and mortality in breast cancer patients. Novel therapeutic agents? are urgently needed. During the past funding cycle, TGFbeta signaling was shown to increase breast cancer cell? production of the osteolytic factor, PTH-rP, and breast cancer cells with attenuated TGFbeta signaling were shown to? cause fewer bone metastases in vivo. TGFbeta has been shown to enhance carcinoma metastasis by acting mainly? in a paracrine fashion. Bone is the body's largest source of TGFbeta, and excessive TGFbeta released from cancer? cells and bone matrix after breast cancer cells metastasize to the bone has been shown to cause osteolytic? lesions via PTHrP. However, the mechanism by which TGFbeta causes increased PTH-rP expression, and whether? TGFbeta antagonists can be useful clinically in the prevention and treatment of breast cancer-mediated bone? metastasis are still relatively unexplored. As such, our Specific Aim 1 will determine the mechanism by which TGFbeta regulates Gli2 expression to test the hypothesis that Gli2 mediates TGFbeta-induced PTH-rP expression and osteolysis. Our preliminary studies also showed that systemic administration of a TGFbeta type I receptor (Rl) kinase inhibitor significantly inhibited bone metastasis of human breast cancer cells in vivo.
Our Specific Aim 2 will thus determine the comparative efficacy of different types of TGFbeta antagonists in inhibiting breast cancer-induced bone metastasis to test the hypothesis that TGFbeta antagonists may have clinical utilities for the treatment of osteolytic bone metastasis. Since abrogation of autocrine TGFbeta signaling has been shown to promote primary tumor growth, it is essential to address whether systemic administration of TGFbeta antagonists will also promote tumorigenicity of premalignant breast cells that possess the autocrine tumor-suppressive activity of TGFbeta. Therefore, our Specific Aim 3 will test the hypothesis that different modes of antagonism against TGFbeta signaling with TGFbeta binders or Rl kinase inhibitors may be exploited to inhibit tumor progression due to excessive paracrine TGFbeta activity while preserving the tumor-suppressive activity of autocrine TGFbeta. Our long-term goals are to elucidate the molecular? mechanisms that drive bone metastasis and osteolysis and to ultimately develop safe, effective TGFbeta antagonists? as novel agents for the prevention and treatment of breast cancer-induced bone metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA040035-19
Application #
7477132
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
19
Fiscal Year
2007
Total Cost
$304,508
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Arnold Egloff, Shanna A; Du, Liping; Loomans, Holli A et al. (2017) Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer. Oncotarget 8:722-741
Arnold, Shanna A; Loomans, Holli A; Ketova, Tatiana et al. (2016) Urinary oncofetal ED-A fibronectin correlates with poor prognosis in patients with bladder cancer. Clin Exp Metastasis 33:29-44
Preston Campbell, J; Mulcrone, P; Masood, S K et al. (2015) TRIzol and Alu qPCR-based quantification of metastatic seeding within the skeleton. Sci Rep 5:12635
Sharma, Ramaswamy; Williams, Paul J; Gupta, Anjana et al. (2015) A dominant-negative F-box deleted mutant of E3 ubiquitin ligase, ?-TrCP1/FWD1, markedly reduces myeloma cell growth and survival in mice. Oncotarget 6:21589-602
Seeley, Erin H; Wilson, Kevin J; Yankeelov, Thomas E et al. (2014) Co-registration of multi-modality imaging allows for comprehensive analysis of tumor-induced bone disease. Bone 61:208-16
Johnson, Rachelle W; Merkel, Alyssa R; Page, Jonathan M et al. (2014) Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer. Clin Exp Metastasis 31:945-59
Ding, Hao; Nyman, Jeffry S; Sterling, Julie A et al. (2014) Development of Raman spectral markers to assess metastatic bone in breast cancer. J Biomed Opt 19:111606
Hansen, Amanda G; Arnold, Shanna A; Jiang, Ming et al. (2014) ALCAM/CD166 is a TGF-?-responsive marker and functional regulator of prostate cancer metastasis to bone. Cancer Res 74:1404-15
Waning, David L; Mohammad, Khalid S; Guise, Theresa A (2013) Cancer-associated osteoclast differentiation takes a good look in the miR(NA)ror. Cancer Cell 24:407-9
Jin, Renjie; Sterling, Julie A; Edwards, James R et al. (2013) Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PLoS One 8:e60983

Showing the most recent 10 out of 210 publications