Relating Diabetes and Cancer
Since Summer 2017, I have worked under Dr. Ann Kimble-Hill in the Indiana University School of Medicine to explore one question: How does Type II Diabetes contribute as a risk to the development of breast cancer?
In the first phase of this inquiry, I implemented a broader study design, looking at the trends in clinical outcomes and genomic data across four different cancers. I had the opportunity to design and implement a study exploring the trends in the mRNA and protein expression of components in the insulin signaling axis. Due to the promise of the study in relating Type II diabetes to trends in clinical outcomes, like mortality and metastasis across four different types of cancers, I had the opportunity to publish a “Systematic Survey of the Role of IGF in the Link Between Diabetes and Cancer” as first-author in Volume IV of the Indiana University Journal of Undergraduate Research (IUJUR).
Through the study, I gained insight on the development of comorbid conditions and the molecular basis of disease.In the second, and ongoing, phase of the research question, I am exploring the lipidomics changes in breast tissue cell lines exposed to elevated glucose levels through fluorescence microscopy. These studies have developed my interest in the management of chronic, comorbid conditions from the molecular level.
Publications
Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer (2020)
Studies have suggested that type 2 diabetes (T2D) is associated with a higher incidence of breast cancer and related mortality rates. T2D postmenopausal women have an ~20% increased chance of developing breast cancer, and women with T2D and breast cancer have a 50% increase in mortality compared to breast cancer patients without diabetes. This correlation has been attributed to the general activation of insulin receptor signaling, glucose metabolism, phosphatidylinositol (PI) kinases, and growth pathways. Furthermore, the presence of breast cancer specific PI kinase and/or phosphatase mutations enhance metastatic breast cancer phenotypes. We hypothesized that each of the breast cancer subtypes may have characteristic PI phosphorylation profiles that are changed in T2D conditions. Therefore, we sought to characterize the PI phosphorylation when equilibrated in normal glycemic versus hyperglycemic serum conditions. Our results suggest that hyperglycemia leads to: 1) A reduction in PI3P and PIP3, with increased PI4P that is later converted to PI(3,4)P2 at the cell surface in hormone receptor positive breast cancer; 2) a reduction in PI3P and PI4P with increased PIP3 surface expression in human epidermal growth factor receptor 2-positive (HER2+) breast cancer; and 3) an increase in di- and tri-phosphorylated PIs due to turnover of PI3P in triple negative breast cancer. This study begins to describe some of the crucial changes in PIs that play a role in T2D related breast cancer incidence and metastasis. View Full-Text
Keywords: hyperglycemia; hormone receptor positive breast cancer; HER2 positive breast cancer; triple negative breast cancer; PI3K/AKT signaling
Epidemiological studies have proposed a link between type II diabetes and cancer via the IGF/insulin signaling pathway, which includes insulin-like peptides (IGF1, IGF2, and insulin), insulin receptors (IR-A, IR-B, IGF1R, and hybrids), and insulin substrate proteins (IRS1–6). In this study, up- and down-regulation of various components in the IGF/insulin signaling pathway are compared to clinical outcomes for cancer patients; the components include diagnosis age, overall survival, tumor invasion and vascularization, and body mass index. It was found that the up-regulation of insulin growth Factor (IGF)/insulin components was associated with overall survival and tumor invasion and vascularization, while the down-regulation of equivalent components was not associated with clinical outcomes assessed in this study. Particularly, the up-regulation of DOK5, IGF2, and IRS2 in colorectal cancer and IGF1R in liver cancer is associated with significantly decreased overall survival. Functional aberrations in either of the two proteins in co-expression pairs were identified for each cancer and correlated with overall survival and diagnosis age. Specific biomarkers proposed in this study will be further analyzed to fine-tune consistent associations that can be translated to reliable prognostic standards for the roles of IGF/insulin signaling pathway modulations that promote cancer.
Keywords: Type II diabetes (T2DM), colorectal cancer, liver cancer, pancreatic cancer, uterine cancer, insulin growth factor (IGF), insulin receptor (IR)