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

Chia J., Kusuma N., Anderson R., Parker B., Bidwell b., Zamurs L., Nice E., Pouliot N.

The American Journal of Pathology, 2007

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.