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Interdisciplinary Biomedical Sciences Program
B.A. 2005, Montclair State University
Thesis Advisor: Teresa Wood, Ph.D.
Dept of Neurology & Neuroscience
Monday, April 21, 2014
1:00 P.M., Cancer Center, G Level Room 1196
The development and maturation of the mammary gland is controlled by a complex interaction of both systemic and local hormones and growth factors. The most common pathology of this tissue is breast cancer, a disease that affects a great number of women and men, and is one of the leading causes of death among women. Despite the challenging nature of breast cancer prevention and treatment, the need for ongoing research toward better understanding of normal mammary gland development and breast carcinogenesis is needed to reduce breast cancer mortalities.
The insulin-like growth factor (IGF) system has known roles in mammary epithelial cell cycle regulation, proliferation and transformation. Furthermore, the IGF system has been implicated in aggressive breast cancer cell lines and tumors. Herein, we demonstrate that loss of the IGF type 1 receptor (IGF-IR) signaling leads to a reduction in mammosphere forming frequency, suggesting a role for IGF signaling in mammary stem and progenitor cell proliferation. To study the role of IGF-1R in tumorigenesis, we established a mouse line (bigenic) carrying the MMTV-Wnt1 transgene and a MMTV-kinase-dead IGF-1R and demonstrated that reduction in signaling through the IGF-1R alters tumor latency and phenotype in the MMTV-Wnt1 mouse basal cell breast cancer model. Bigenic tumors had increased expression of epithelial-mesenchymal transition marker(s), a decrease in luminal differentiation marker(s), as well as, an increase in lung metastasis compared to MMTV-Wnt1 tumors. Furthermore, we demonstrated that acute pharmacological inhibition of the IGF-IR in MMTV-Wnt1 tumor cells increases tumorsphere-forming frequency in vitro.
Bigenic tumors had increased insulin receptor isoform A to insulin receptor isoform B (IR-A:IR-B) ratio and expression of IGF-II; IGF-II stimulation of the IR-A in vitro increased beta-catenin protein levels, a read-out of canonical Wnt signaling. These findings support the conclusion that loss of IGF-IR and increased signaling through IR-A in the context of heightened Wnt signaling, leads to accelerated tumorigenesis and a more aggressive tumor phenotype via the enhancement of canonical Wnt signaling. Finally, we provide evidence for a model through which IR-A signaling enhances canonical Wnt signaling by phosphorylating the canonical Wnt co-receptor Lrp-6.