Therapeutic Targeting of Integrin αvβ6 in Breast Cancer

Abstract

BackgroundIntegrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.MethodsProtein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.ResultsHigh expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.ConclusionsTargeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.

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

“…found that approximately 15–16% of the London and Nottingham cohort had detectable α v β 6 integrin expression 14. Our ROC analysis of the KMIO‐CS of α v β 6 integrin protein versus ITGB6 transcript levels had yielded a good concordance (AUC = 0.83; P  < 0.0001) with 93% specificity.…”

“…Scoring of integrin α v β 6 was done as reported by Moore et al. 14 in their supplementary data. TMA cores with less than 100 invasive tumor cells were considered inadequate for interpretation and were dropped from further scoring.…”

“…A recent study carried out by Moore et al. has reported the involvement of α v β 6 in metastatic progression of HER2 overexpressing breast tumors 14. This cooperation between integrins and RTKs leads to activation of the canonical Rho–Rac pathway through a large number of mechanisms.…”

“…In an evolving tumor, the stromal cues bring about changes in the extracellular matrix leading to activation of a family of integrins that mediate attachment of tumor cells to the extracellular matrix (ECM) 13. Components of the ECM, like fibronectin and tenascin and the latency‐associated peptide 1 and 3 have been shown to activate α v β 6 integrin leading to local activation of TGF β 1 signaling at tumor‐stroma interface facilitating tumor migration and invasion 14, 15, 16, 17.…”

Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue

“…Integrin beta 6 mRNA expression, which is 7.7-fold higher in this subpopulation, has been shown as an independent predictor of survival, and high expression is associated with distant metastasis and poor survival in breast cancer (58) as well as in colon cancer where it also appears to confer chemoresistance (59). A number of upregulated secreted factors with roles in cancer metastasis, angiogenesis, and hypoxia (e.g., TGFB1, LOXL4, WNT4) add to the interpretation that these cells communicate actively with their surrounding and may have a more significant role in the interaction with the TME than their CD184 hi counterparts.…”