Evidence for a role of tumor-derived laminin-511 in the metastatic progression of breast cancer

Most studies investigating laminins (LMs) in breast cancer have focused on LM-111 or IM-332. Little is known, however, about the expression and function of alpha 5 chain-containing LM-511/521 during metastatic progression. Expression of LM-511/521 subunits was examined in genetically related breast tumor lines and corresponding primary tumors and metastases in a syngeneic mouse model using real-time quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. The results from our investigation indicate that LM-511 rather than LM-111, -332, or -521 correlates with metastatic potential in mouse mammary tumors. LM-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 alpha 3 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 LM-511 primarily via alpha 3 beta 1 integrin, results from antibody perturbation experiments and flow cytometry analysis suggest that this response is mediated by an as yet unidentified alpha 3 beta integrin heterodimer (other than alpha 3 beta 1) in MDA-MB-231 cells. These results are consistent with earlier reports implicating a3 integrins in breast cancer progression and support the role of LM-511 as a functional substrate regulating breast cancer metastasis.