Browsing by Subject "Laboratory Medicine & Pathology"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Genetic Approach to Generating a Novel Mouse Model of Mammary Tumorigenesis
    (2011-04-13) Miller, Matthew
    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.
  • Thumbnail Image
    Item
    Mechanisms of Androgen-Mediated Repression of the Maspin Tumor Suppressor Gene in Prostate Cancer
    (2010-04-21) Bader, David
    Prostate Cancer (PCa) is the second leading cause of cancer death in American men; one in six will be diagnosed with the disease during his lifetime. The androgen receptor (AR) is a transcription factor necessary for normal prostate cell growth as well as for growth of PCa. When AR is activated by androgens, it translocates to the nucleus and exerts transcriptional activation and repression of target genes. Significant efforts have focused on characterizing genes that are activated by AR such as prostate specific antigen (PSA), a marker for PCa screening. Genes that are transcriptionally repressed by AR are also likely to play a role in the progression of prostate cancer, yet the mechanisms behind their repression have received less attention. One such gene is maspin, a tumor suppressor gene that is repressed by androgens. Maspin expression is associated with increased cellular adhesion, increased sensitivity to cellular apoptosis, and decreased angiogenesis in the tumor microenvironment. In this study, we demonstrated that (1) Maspin is repressed following androgen treatment, (2) the repression is mediated in a direct manner, and (3) Androgen antagonists such as bicalutamide do not affect the ability of AR to repress maspin. Ongoing research will continue to investigate AR’s role in the repression of maspin. Understanding the underlying mechanisms by which AR represses maspin and other target genes may reveal novel opportunities for developing new prostate cancer therapies.