Abstract
BackgroundExpression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3β1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3β1 and COX2 by testing for their correlated expression among various forms of human breast cancer.MethodsImmunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman’s rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria.ResultsAlthough expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (rs = 0.49, p < 0.001, n = 59) and archived samples (rs = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage.ConclusionsCOX2 and α3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin α3β1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of α3β1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target α3β1, and that α3 expression might serve as an independent prognostic biomarker.
Highlights
Expression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer
Positive staining for the α3 subunit is directly reflective of integrin α3β1 expression, as β1 is the only integrin β subunit with which the α3 subunit dimerizes [3]
Our current findings support the inhibition of integrin α3β1 as a promising therapeutic strategy, as this approach may provide an alternative mode of suppressing COX2 without the adverse side effects that have been associated with direct COX2 inhibitors
Summary
Expression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Integrins function as bidirectional signaling receptors that regulate both cellular responses to cues from the tissue microenvironment and cell-mediated changes to the microenvironment, and integrin signaling in tumor cells is known to be critically important for promoting malignant growth and metastasis [1,2,3,4,5]. A number of studies have shown that α3β1 promotes tumor growth, invasion, and/ or metastasis of breast cancer or other carcinoma cells [11,12,13,14,15]. Two major ECM ligands for α3β1, laminin-332 and laminin-511, are often over-expressed in breast and other carcinomas, and both of these laminins have been linked to tumor invasion and metastasis [16,17,18,19,20]. One group’s recent analysis of the Breast Invasive Carcinoma TCGA database revealed a link between decreased patient survival and co-upregulation of the genes encoding the integrin α3 subunit (ITGA3) and the laminin α5 chain (LAMA5) [15]
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