High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

Abstract

Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho–Rac pathway including downstream genes (ACTR2,ACTR3) and effector proteinases (MMP9,MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2‐ and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 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 ITGB6 levels (HR = 2.9 (0.9–8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node‐positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho–Rac pathway through increased expression of MMP9 and MMP15.

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…Numerous studies have implicated Rac/PAK activities with the maintenance of mesenchymal stem cell-like populations in epithelial cancers; and thus, therapy resistance (Zhao et al, 2011;Ong et al, 2013;Zhu et al, 2015;Goel et al, 2016;Huynh et al, 2016;Aboukameel et al, 2017;Lai et al, 2017;Morrison Joly et al, 2017;Cardama et al, 2018;Goka et al, 2019). Specifically in breast cancer, Rac/Cdc42/PAK signaling is implicated with therapy resistance of HER2-type (Wang et al, 2006;Ebi et al, 2013;Laurin et al, 2013;Dokmanovic et al, 2014;Desai et al, 2016;Hampsch et al, 2017), triple negative (De et al, 2017), and ER(+) cancers (Cai et al, 2003;Gonzalez et al, 2017). TCGA data show that Rac1 or PAK1 overexpression is associated with malignant breast cancer and significantly diminishes HER2 type patient survival within 10 years following diagnosis (Fang et al, 2016).…”

Gene isoforms as expression-based biomarkers predictive of drug response in vitro

“…Previous reports showed that the interaction between integrins and several receptor tyrosine kinases like HER2 and EGFR leads to a crosstalk between signaling events that have been implicated in tumor progression and metastasis 39 , 40 . Desai et al 41 recently identified a significant positive correlation between ITGB6 and EGFR proteins, suggesting that ITGB6 and EGFR are interacting, and that ITGB6 isoform expression sensitizes cells towards erlotinib, an EGFR inhibitor.…”

Evaluation of the mRNA expression levels of integrins α3, α5, β1 and β6 as tumor biomarkers of oral squamous cell carcinoma

“…(total=55) Mean ± SD P-value a Mean ± SD P-value a Mean ± SD P-value a Mean ± SD P-value a A, All locations cancer (37). However, to the best of our knowledge, these integrin biomarkers have rarely been investigated in OSCC.…”