The Role of Cell Cycle Mediators in the Progression of Non-alcoholic Steatohepatitis in Male and Female Murine Models

Hepatocellular carcinoma (HCC) is the most prevalent primary cancer of the liver and one of the leading causes of cancer-related deaths worldwide. There are a multitude of risk factors that contribute to the development of HCC including viral infection, obesity, alcoholism, as well as non-alcoholic steatohepatitis (NASH). In the case of these chronic diseases and repeated injury, the liver continuously repairs itself to maintain its structural integrity, resulting in fibrosis, and in more serious cases, cirrhosis– major risk factors in the development of HCC. Men are 3-5x more likely to develop liver cancer than women; however, the exact mechanism for this remains undetermined. Previous work in our lab using a transgenic mouse model overexpressing the cyclin-like protein Spy1 showed an increased incidence of HCC and decrease in rates of fibrosis, suggesting a link between cell cycle regulation and progression to HCC. Spy1 binds and activates CDKs at the G1-S and G2-M checkpoints, leading to cell cycle progression independent of cyclin-based regulation. Using a methionine-choline deficient diet to induce NASH, the role of various cell cycle mediators will be investigated to uncover the link between cell cycle regulation and NASH disease progression. In addition, differences between female and male mouse responses to the diet with respect to cell cycle regulation will be analyzed. A better understanding of the relationship between cell cycle regulation and NASH disease progression in both female and male mouse models will help identify novel diagnostic markers and pathways of therapeutic importance in HCC

The Role of Spy1 During Mammary Involution

One in eight women will be diagnosed with breast cancer in her lifetime. From puberty to menopause, risk of breast cancer fluctuates with the natural development of the breasts. A period of increased breast cancer risk, metastatic potential, and mortality occurs following childbirth. Recent preliminary research suggests the propensity of postpartum breast cancer (PPBC) is enabled by the natural process of involution: when the mammary gland reverts to non-lactating tissue by balancing high rates of cell death regeneration via stem cells. This death and regeneration are controlled by the cell cycle; a particular cell cycle regulator, the atypical protein Spy1, is capable of enabling cell proliferation, protecting stem cells, and overriding cell death. Spy1 levels have been found to be elevated in all forms of breast cancers. Interestingly, levels of Spy1 are similarly elevated during involution. We hypothesize that Spy1 protects the stem cell population necessary for normal mammary gland reconstitution post involution. This project aims to establish Spy1 manipulated involution models by mimicking pregnancy-lactation-involution hormonal cues in vitro and investigate how Spy1 affects mammary gland changes during involution in vivo to determine the effect of Spy1 on mammary stem cells during involution. Understanding Spy1-involution dynamics may reveal how its alterations may potentially lead to aggressive PPBC – beginning the characterisation of this unique subtype and highlighting Spy1 as a target for screening, diagnostic, and treatment. Increasing the scope of postpartum maternal care to include breast cancer perspectives is crucial for improving the care and outcome of PPBC patients

A retrospective single center study investigating the clinical significance of grade in triple negative breast cancer .

Background: Triple negative breast cancer (TNBC) is a heterogenous cancer type which lacks the receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor receptor (HER-2) proteins. Comparatively, HER-2 positive cancers currently have a 7 year disease-free survival rate of 93% while in triple negative breast cancers, it can be as low as 77%. Purpose: While histological tumor grade or the degree of similarity to normal cells is an important prognostic factor (overall outcome), there is limited information on its predictive value (effect of specific therapeutic intervention). This project aimed to investigate the predictive value of grade in triple negative breast cancer for clinical decision making regarding treatment. Experimental Design: We reviewed 305 patient charts of triple negative breast cancer patients from 2004-2017 at Windsor Regional Cancer Center and the significance of grade with respect to oncological variables, survival-time, and time to relapse were explored. Results: The overall survival rates were 90.12%, 64.4%, and 77.2%, for grade 1, 2, 3 respectively. Comparing only between grade 2 and grade 3, we found that after five years, grade 2 patients had a 5.5-fold increased risk of death (HR = 5.5; 95% CI 1.2-25.6) and 2-folds higher risk of relapse (HR= 1.9; 95% CI 1.1-3.2). Grade 3 does significantly better than grade 2 in time to relapse with relapse rates of 70%, 55.6 %, and 75.6%, respectively for grades 1, 2, and 3 (P= 0.04). Conclusion: Grade can be shown to have positive predictive value in determining relapse with grade 2 showing poorest disease-free survival and faster time to relapse after the 5-year mark with implications in stratifying patients by grade in future clinical trials as further research elucidates more information about molecular differences between grades, as an explanation for these findings