High expression of integrin β 6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER 2 amplified breast cancers

Integrin α v β 6 is involved in the transition from ductal carcinoma in situ ( DCIS ) to invasive ductal carcinoma ( IDC ) of the breast. In addition, integrin β 6 ( ITGB 6) is of prognostic value in invasive breast cancers, particularly in HER 2+ subtype. However, pathways mediating the activity of integrin α v β 6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens ( N = 460) for the expression of integrin β 6 ( ITGB 6) mRNA by qPCR . In addition, we have examined a subset ( N = 147) for the expression of α v β 6 integrin by immunohistochemistry ( IHC ). The expression levels of members of Rho–Rac pathway including downstream genes ( ACTR 2 , ACTR 3 ) and effector proteinases ( MMP 9 , MMP 15 ) were estimated by qPCR in the HER 2+ subset ( N = 59). There is a significant increase in the mean expression of ITGB 6 in HER 2+ tumors compared to HR + HER 2‐ and triple negative ( TNBC ) subtypes ( P = 0.00). HER 2+ tumors with the highest levels (top quartile) of ITGB 6 have significantly elevated levels of all the genes of the Rho–Rac pathway ( P ‐values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease‐free survival compared to the group with lower ITGB 6 levels ( HR = 2.9 (0.9–8.9), P = 0.05). The mean level of ITGB 6 expression is increased further in lymph node‐positive tumors. The increased regional and distant metastasis observed in HER 2+ tumors with high levels of ITGB 6 might be mediated by the canonical Rho–Rac pathway through increased expression of MMP 9 and MMP15.