Investigating the effects of CSF-1R and PI3Kdelta inhibition on a breast cancer bone metastasis model

Development of breast cancer-induced bone loss depends on the activation of osteoclasts by tumor-derived factors that promote osteoclastogenesis and osteolysis. The PI3K pathway is activated by several of these factors, in particular CSF-1. Given the ability of PI3K signaling to promote osteoclast survival and activity in a CSF-1R dependent manner, we hypothesized that inhibition of CSF-1R or PI3K signaling with compounds GW2580 and ABT-869, and IC87114, respectively, would decrease osteoclast development and activity leading to decreased osteolysis. Using bioluminescence imaging and μCT, we identified that GW2580 and ABT-869 significantly decreased osteolytic lesions and tumor growth in MDA-MB-231 bone metastases. Also, GW2580 increased bone mass in normal C57BL/6 mice, validating the effect of this inhibitor on CSF-1R-expressing osteoclasts in vivo. Since IC87114 failed to reduce tumor growth and osteolytic damage, we concluded that CSF-1R signaling, independent of PI3K p110δ signaling, contributes significantly to tumor growth and to tumor-induced osteolysis in this model.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Biochemistry and Molecular Biology

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2013

Author dc:creator

• Salazar-Arcila, Carolina

Advisor dc:contributor.advisor

• Jirik, Frank

• Oncology
• Biochemistry

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/26639

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/454