Collagen XIII in breast cancer
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Leena Palotie Audiotrium 101A (Aapistie 5A)
Topic of the dissertation
Collagen XIII in breast cancer
Doctoral candidate
Licentiate of Medicine Charlotta Henriksson
Faculty and unit
University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM and hypoxia
Subject of study
Medicine
Opponent
Associate professor Tuula Kallunki, University of Copenhagen
Custos
Professor Taina Pihlajaniemi, University of Oulu
Collagen XIII in breast cancer
Breast cancer is the most common cancer type among women worldwide and the incidence rates are increasing. Over the past years breast cancer treatments have evolved, but new biomarkers and drug targets are needed to improve therapeutic measures. Collagen XIII (ColXIII) is involved in cell adhesion and its expression is induced during malignant transformation in various tumors, including breast cancer. While ColXIII is a transmembrane collagen, it can also be proteolytically cleaved by furin pro-protein convertase enzymes to yield a shed ectodomain, which is incorporated into the pericellular matrix. The aim of this PhD thesis was to study the role and mechanism of ColXIII in breast cancer, also addressing the potentially different functions of the membrane-bound and shed ectodomain in mammary carcinogenesis. The study was carried out by using various mouse models, multiple human breast cancer cell lines, and an open human breast cancer database.
In the transgenic MMTV-PyMT mammary carcinoma mouse model the proportion of shed ColXIII increased along tumor progression. Knocking out the Col13a1 gene in the MMTV-PyMT model resulted in delayed primary tumor growth, reduced metastasis formation and prolonged overall survival. The lack of shed ColXIII in this mouse model with a deletion of the furin pro-protein convertase recognition sequence reduced metastasis in the MMTV-PyMT model but did not significantly affect primary tumor growth. The absence of ColXIII led to cystic lesions in the hyperplastic mammary tumors and this phenotype was even more striking when only the transmembrane form of ColXIII was synthesized. In addition, the mammary tumors of these two Col13a1 mutants were more differentiated than those in the wild type MMTV-PyMT mice. Reciprocal orthotopical tumor cell transplantations suggested microenvironmental roles for ColXIII in breast cancer.
ColXIII expression was highly upregulated in human triple negative breast cancer cell lines compared to cell lines representing other subtypes. Both CRISPR/Cas9-based knockout and siRNA-based knockdown of ColXIII in MDA-MB-231 cells significantly reduced their proliferation and migration. Experiments with ColXIII conditioned media activated the mitogen-activated protein kinase signaling pathways in luminal A-type MCF-7 cells but did not alter the proliferation or migration of these cells.
In the transgenic MMTV-PyMT mammary carcinoma mouse model the proportion of shed ColXIII increased along tumor progression. Knocking out the Col13a1 gene in the MMTV-PyMT model resulted in delayed primary tumor growth, reduced metastasis formation and prolonged overall survival. The lack of shed ColXIII in this mouse model with a deletion of the furin pro-protein convertase recognition sequence reduced metastasis in the MMTV-PyMT model but did not significantly affect primary tumor growth. The absence of ColXIII led to cystic lesions in the hyperplastic mammary tumors and this phenotype was even more striking when only the transmembrane form of ColXIII was synthesized. In addition, the mammary tumors of these two Col13a1 mutants were more differentiated than those in the wild type MMTV-PyMT mice. Reciprocal orthotopical tumor cell transplantations suggested microenvironmental roles for ColXIII in breast cancer.
ColXIII expression was highly upregulated in human triple negative breast cancer cell lines compared to cell lines representing other subtypes. Both CRISPR/Cas9-based knockout and siRNA-based knockdown of ColXIII in MDA-MB-231 cells significantly reduced their proliferation and migration. Experiments with ColXIII conditioned media activated the mitogen-activated protein kinase signaling pathways in luminal A-type MCF-7 cells but did not alter the proliferation or migration of these cells.
Last updated: 23.1.2024