Date of Final Oral Examination (Defense)
Type of Culminating Activity
Doctor of Philosophy in Biomolecular Sciences
Cheryl L. Jorcyk, Ph.D.
Daniel Fologea, Ph.D.
Richard S. Beard, Ph.D.
Julie Oxford, Ph.D.
Breast cancer has the highest prevalence of cancers in women in the USA; approximately 1 in 8 women will receive a diagnosis in their lifetime. Invasive ductal carcinoma (IDC) is the most commonly diagnosed breast cancer and presents a serious problem if it metastasizes, decreasing 5-year patient survival from ~98% to ~29%. Tumor cells grow in an environment that is known as the tumor microenvironment (TME). Due to inflammation, the TME of IDC is often saturated with neutrophil- and macrophage-derived proinflammatory cytokines including oncostatin M (OSM) and interleukin-1beta (IL-1β), both of which promote favorable conditions for metastasis. Modifications in the organization, density, and alignment of collagen I fibers present in extracellular matrix (ECM) of the TME directly impact IDC cell motility and invasiveness, both factors in metastasis. Lysyl oxidase like-2 (LOXL2) is an enzymatic protein secreted by fibroblast and IDC cells that catalyzes the crosslinking of collagen I fibers in the ECM. Increased collagen crosslinking alters the characteristics mentioned above, worsening patient prognosis and promoting metastasis. Proposed is a novel mechanism for proinflammatory cytokine-promoted ECM remodeling and subsequent metastasis in IDC. OSM signaling induces enzymatically active LOXL2 expression and extracellular secretion, leading to significant remodeling of ECM collagen I fibers that promotes significantly increased invasion, tumor growth, and metastasis. LOXL2-mediated ECM remodeling is also critical for OSM promoted IDC tumor growth and metastatic progression. Combined, these results demonstrate that OSM-induced LOXL2 has serious implications for IDC tumor progression and metastasis. Further studies and understanding of the mechanisms at play in this association will hopefully lead to better therapeutic discoveries to prevent metastases.
Dinca, Simion C., "Mechanics for Inflammatory Cytokine-Promoted Breast Cancer Progression: OSM-Induced LOXL2 Leads to Extracellular Matrix Remodeling of Collagen I and Subsequent Metastasis" (2023). Boise State University Theses and Dissertations. 2054.
Available for download on Thursday, July 11, 2024