Collagen XVIII in growth and treatment of breast cancer

Breast cancer is the most common cancer amongst women and accounts for almost 2.1 million new cases and more than 0.5 million deaths every year worldwide. Despite progress in targeted molecular therapies, resistances to new drugs is a major challenge in cancer care. Solid tumors consist of cancer cells and other cells in the tumor microenvironment, and the surrounding extracellular matrix. Many of the proteins that support the structure of the extracellular matrix, such as various collagens, actively regulate cancer growth and progression. Type XVIII collagen is produced in solid tumors, where its abundance correlates with the progression of cancer. However, it is unclear by which mechanism collagen XVIII promotes tumor malignancy. In this PhD study, the significance of collagen XVIII in breast cancer was studied using human cancer tissue samples, cell and mouse models and bioinformatics methods. The abundance of collagen XVIII in cancer cells was found to predict a poor prognosis for the patient. Collagen XVIII was found to regulate the activity of growth factor receptors which mediate the growth signal to cancer cells and promote to the proliferation and migration of cancer cells. Collagen XVIII was also found to enhance the stem cell characteristics of cancer cells which are thought to maintain cancer growth and promote the development drug resistance. A significant finding showed that in preclinical cell and mouse experiments inhibition of collagen XVIII activity enhanced the effect of EGFR/ErbB growth factor receptor-targeting anti-cancer drugs. In summary, the study demonstrated that collagen XVIII is a promising target for drug development. The results predict a potential to exploit collagen XVIII measurements in cancer diagnostics to predict patients’ outcome and guide the treatments. In addition, inhibition of collagen XVIII may be utilized in the treatment of breast cancer to improve the efficacy of certain targeted drugs, even when cancer cells develop a resistance to these drugs.