Evidence for a Role of Tumor-Derived Laminin-511 in the Metastatic Progression of Breast Cancer

Here, the authors investigate the expression and function of alpha5 chain-containing laminins, laminin-521 and laminin-511, during metastatic progression. Expression of laminin-511/laminin-521 subunits was examined in genetically related breast tumor lines and corresponding primary tumors and metastases in a syngeneic mouse model. The results indicate that laminin-511 rather than laminin-111, -332, or -521 correlates with metastatic potential in mouse mammary tumors. Current evidence argues against a direct role for laminin-111 and laminin-332 in the late-stage progression of breast tumors because both isoforms are down-regulated in most advanced breast tumors, suggesting a tumor-suppressing role and it is unlikely that these isoforms are used directly by breast tumor cells to promote invasion and metastasis. Laminin-511 was a potent adhesive substrate for both murine and human breast carcinoma cells and promoted strong haptotactic responses in metastatic lines. Haptotaxis was mediated by alpha3 integrin in both MCF-7 and MDA-MB-231 cells and was strongly inhibited by blocking antibodies against this integrin subunit. However, whereas nonmetastatic MCF-7 cells migrated toward laminin-511 (primarily via a3β1 integrin), results suggest that this response is mediated by an as yet unidentified a3β integrin heterodimer in MDA-MB-231 cells. These results are consistent with earlier reports implicating a3 integrins in breast cancer progression and support the role of laminin-511 as a functional substrate regulating breast cancer metastasis.