Abstract
BackgroundIncreased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis.MethodsWe analyzed the association of collagen XIII expression with breast cancer development and metastasis using published gene expression profiles generated from human breast cancer tissues. Utilizing gain- and loss- of function approaches and 3D culture assays, we investigated roles of collagen XIII in regulating invasive tumor growth. Using the tumorsphere/mammosphere formation assay and the detachment cell culture assay, we determined whether collagen XIII enhances cancer cell stemness and induces anoikis resistance. We also inhibited collagen XIII signaling with β1 integrin function-blocking antibody. Finally, using the lung colonization assay and the orthotopic mammary tumor model, we investigated roles of collagen XIII in regulating breast cancer colonization and metastasis. Cox proportional hazard (log-rank) test, two-sided Student’s t-test (two groups) and one-way ANOVA (three or more groups) analyses were used in this study.ResultsCollagen XIII expression is significantly higher in human breast cancer tissue compared with normal mammary gland. Increased collagen XIII mRNA levels in breast cancer tissue correlated with short distant recurrence free survival. We showed that collagen XIII expression promoted invasive tumor growth in 3D culture, enhanced cancer cell stemness, and induced anoikis resistance. Collagen XIII expression induced β1 integrin activation. Blocking β1 integrin activation significantly reduced collagen XIII-induced invasion and mammosphere formation. Importantly, silencing collagen XIII in MDA-MB-231 cells reduced lung colonization and metastasis.ConclusionsOur results demonstrate a novel function of collagen XIII in promoting cancer metastasis, cell invasion, and anoikis resistance.
Highlights
Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients
We showed that expression of collagen XIII is higher in breast cancer tissue compared with normal mammary gland, and that the increased mRNA level of collagen XIII in cancer tissue is associated with poor prognosis and cancer metastasis
By analyzing TCGA and Finak datasets, we found that collagen XIII mRNA levels were significantly increased in human breast cancer tissue compared to normal mammary gland tissue (Fig. 1b, c)
Summary
Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients [3]. The transgenic mice with increased collagen deposition in mammary tissue have a three-fold increase in tumor formation. The extracellular matrix (ECM) surrounding a breast tumor is more dense or stiff from increased collagen deposition and crosslink [12]. These researches indicate that increased collagen expression and deposition promotes breast cancer development and progression by enhancing tumor growth and invasion
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