Genetic Approach to Generating a Novel Mouse Model of Mammary Tumorigenesis

Abstract

Fibroblast growth factor receptors (FGFRs) and their ligands contribute to cellular functions including proliferation, survival, differentiation, migration, and angiogenesis. The growth factor receptor, FGFR1, chromosomal locus is amplified in 10% of breast cancer patients. Patients with this amplification do not respond well to current therapies and have been shown to develop a resistance to endocrine therapies, thus the inducible fibroblast growth factor receptor-1 (iFGFR1) was engineered. When activated, iFGFR1 promotes increased lateral budding of epithelial structures which develop into hyperplasias that progress to multicellular invasive lesions, characteristic of breast cancer. One pro-inflammatory protein upregulated by iFGFR1 activation is osteopontin. Osteopontin is a secreted glycophosphoprotein that is involved in a variety of different cancer types, including breast cancer. Data suggests that osteopontin is synthesized by breast carcinomas and acts to promote traits associated with increased aggressiveness. To study iFGFR1-induced osteopontin expression and the role osteopontin plays in cancer development and progression in mouse mammary glands in vivo, I developed a novel mouse model where mice are heterozygous for our FGFR transgene and osteopontin null (FGFR1 +/-; osteopontin -/-). In order to do this I backcrossed osteopontin -/- mice on a C57BL/6 genetic background to the FVB genetic background of the FGFR1 mice. The goal of this project was to master techniques in mouse husbandry and PCR-based genotyping as well as tissue staining. With the new transgenic mouse model we can better study the correlation between osteopontin levels and breast cancer in hopes of making osteopontin a targetable factor for therapeutic intervention.