Integrin α3β1-CD151 complex regulates dimerization of ErbB2 via RhoA

Integrin alpha 3 beta 1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of alpha 3 beta 1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of alpha 3 beta 1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of alpha 3 beta 1-depleted cells was reproduced upon depletion of tetraspanin CD151 and mirrored that of the cells treated with Herceptin, an established ErbB2 antagonist. Breast cancer cells expressing the alpha 3 beta 1-CD151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with alpha 3 beta 1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in alpha 3 beta 1-CD151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both alpha 3 beta 1 and CD151. We also found that the level of active RhoA was increased in alpha 3 beta 1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of alpha 3 beta 1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of alpha 3 beta 1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the alpha 3 beta 1-CD151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression.