Identification of molecular determinants of primary and metastatic tumour re-initiation in breast cancer

Abstract

Through in vivo selection of multiple ER-negative human breast cancer populations for enhanced tumour-forming capacity, we have derived subpopulations that generate tumours more efficiently than their parental populations at low cell numbers. Tumorigenic-enriched subpopulations exhibited increased expression of LAMA4, FOXQ1 and NAP1L3—genes that are also expressed at greater levels by independently derived metastatic subpopulations. These genes promote metastatic efficiency. FOXQ1 promotes LAMA4 expression, and LAMA4 enhances clonal expansion following substratum detachment in vitro, tumour re-initiation in multiple organs, and disseminated metastatic cell proliferation and colonization. The promotion of cancer cell proliferation and tumour re-initiation by LAMA4 requires β1-integrin. Increased LAMA4 expression marks the transition of human pre-malignant breast lesions to malignant carcinomas, and tumoral LAMA4 overexpression predicts reduced relapse-free survival in ER-negative patients. Our findings reveal common features that govern primary and metastatic tumour re-initiation and identify a key molecular determinant of these processes.