From Population to Protein: A Characterization of Inflammatory Breast Cancer via Epidemiology and Molecular Biology

Abstract

Inflammatory breast cancer (IBC) is a rare and extremely aggressive form of breast cancer, with high rates of metastasis at diagnosis and a relative 5-year survival rate of about 40%. There are currently no clinically validated molecular markers of IBC, leading both to difficulty in diagnosing IBC and to a lack of targeted therapies. Therefore, there is pressing need for a standard method of coding and recording IBC cases based on current knowledge of IBC in order to determine up-to-date prognoses for IBC survival. There is also need for a deeper understanding of molecular drivers of IBC’s aggressively metastatic phenotype in order to develop treatments that could further improve survival outcomes. In this work, we aim to 1) develop and utilize a clinically-relevant coding method to assess IBC incidence and survival in the US over four decades, and 2) determine the effects of candidate molecular markers RhoC, epithelial junction proteins, and type I interferons on IBC and other aggressive breast cancers’ invasive potential. We find that using the clinical signs of edema, erythema, and “peau d’orange” to define IBC cases in the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) databases results in a cohort of patients with nearly identical survival curves compared to IBC cases defined by specifically stated pathologic or clinical diagnosis of IBC in the tumor registry record. We further report that the incidence of IBC has been largely stable over the past four decades, while IBC survival measured in mean survival months has significantly improved, doubling over the past three decades. However, we find significant racial disparities in the epidemiology of IBC; black patients have higher incidence, younger age at diagnosis, and worse survival of IBC compared to white patients. Despite overall improved survival for all races, the differences in survival between black and white patients have persisted from the 1980s to the 2010s. To explore potential molecular therapeutic targets that could be utilized to further improve survival outcomes for IBC patients, we move to assessing IBC from a cell biology perspective by using CRISPR-Cas9 knockout of RhoC, a small GTPase highly expressed in IBC and other aggressive breast cancers, to investigate the mechanism behind RhoC-driven metastasis. We determine that in these breast cancer cells, RhoC expression promotes cell invasion while decreasing the expression of cell-cell junction proteins and the functionality of epithelial junctions. RhoC expression also increases robust cellular Type I interferon signaling and response to interferon treatment, especially in triple-negative breast cancer cells. We further find that interferon treatment increases cell-cell adhesion and decreases cellular invasiveness, but these effects are dampened in RhoC knockout cells. Overall, this thesis work contributes an updated picture of the state of IBC incidence and survival in the US, as well as a novel mechanistic linkage between RhoC, Type I interferon signaling, and epithelial junction proteins that could be useful in developing therapeutic interventions for metastatic IBC.