Integrin α3β1 Can Function to Promote Spontaneous Metastasis and Lung Colonization of Invasive Breast Carcinoma

Zhou, Bo; Gibson‐Corley, Katherine N.; Herndon, Mary E.; Sun, Yihan; Gustafson-Wagner, Elisabeth; Teoh-Fitzgerald, Melissa; Domann, Frederick E.; Henry, Michael D.; Stipp, Christopher S.

doi:10.1158/1541-7786.mcr-13-0184

Cited by 56 publications

(52 citation statements)

References 74 publications

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“…Indeed, while shRNA-mediated silencing of α3β1 in breast cancer cells reduced cell invasion in vitro and tumor growth in vivo [11,15], similar silencing of α3β1 enhanced lung metastasis in an in vivo model of prostate cancer [53]. Moreover, α3β1 expression varied considerably among breast tumors, as shown here and by others [12,38].…”

Section: Discussionsupporting

confidence: 52%

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 52%

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

et al. 2014

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“…For example, α 3 β 1 integrin binding is known to mediate lung metastasis in rats and mice. 18,19 However, high α 3 integrin gene expression showed only a non-significant correlation with lung metastasis, and only when we isolated the analysis to triple negative patients. Across all subtypes of patients, high α 3 integrin gene expression actually more highly correlated with bone metastasis (Fig.…”

Section: Discussionmentioning

confidence: 98%

A cell–ECM screening method to predict breast cancer metastasis

et al. 2015

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Breast cancer preferentially spreads to the bone, brain, liver, and lung. The clinical patterns of this tissue-specific spread (tropism) cannot be explained by blood flow alone, yet our understanding of what mediates tropism to these physically and chemically diverse tissues is limited. While the microenvironment has been recognized as a critical factor in governing metastatic colonization, the role of the extracellular matrix (ECM) in mediating tropism has not been thoroughly explored. We created a simple biomaterial platform with systematic control over the ECM protein density and composition to determine if integrin binding governs how metastatic cells differentiate between secondary tissue sites. Instead of examining individual behaviors, we compiled large patterns of phenotypes associated with adhesion to and migration on these controlled ECMs. In combining this novel analysis with a simple biomaterial platform, we created an in vitro fingerprint that is predictive of in vivo metastasis. This rapid biomaterial screen also provided information on how β1, α2, and α6 integrins might mediate metastasis in patients, providing insights beyond a purely genetic analysis. We propose that this approach of screening many cell–ECM interactions, across many different heterogeneous cell lines, is predictive of in vivo behavior, and is much simpler, faster, and more economical than complex 3D environments or mouse models. We also propose that when specifically applied toward the question of tissue tropism in breast cancer, it can be used to provide insight into certain integrin subunits as therapeutic targets. Insight, innovation, integration We developed a high-throughput method to rapidly screen cell adhesion, motility, and growth factor responses on biomaterial surfaces. This approach is analogous to systems biology, relying on cell phenotypes in lieu of genetics. We used this technique to reveal patterns of phenotypes associated with breast cancer metastasis to possible tissue sites (bone, brain, lung). By comparing the phenotypic patterns between cell lines that metastasize to only one tissue site with heterogeneous cell lines, we provide the first method to connect in vitro phenotype to in vivo fate. This method is successful without genetic analysis, yet it also predicts outcomes related to integrin gene expression, potentially identifying new targets for tissue-specific metastasis.

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“…Factors that influence whether α3β1 promotes or restrains tumor progression may include (i) whether the tumor secretes an α3β1 integrin ligand (38), (ii) the stage at which tumor progression is being modeled (39), (iii) the role of α3 integrin in controlling mRNA splicing (41), and (iv) the downstream signaling pathways driving malignant progression. For example, α3β1 promotes Rac activation (42), even as it limits Rho activity, and is required for Rac-driven mammary tumors (40), even as it restrains Rho-driven prostate carcinomas, as we show here.…”

Section: Discussionmentioning

confidence: 99%

α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

Varzavand

Hacker

et al. 2016

Cancer Research

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Existing anti-cancer strategies focused on disrupting integrin functions in tumor cells or tumor-involved endothelial cells have met limited success. An alternative strategy is to augment integrin-mediated pathways that suppress tumor progression, but how integrins can signal to restrain malignant behavior remains unclear. To address this issue, we generated an in vivo model of prostate cancer metastasis via depletion of α3β1 integrin, a correlation observed in a significant proportion of prostate cancers. Our data describe a mechanism whereby α3β1 signals through Abl family kinases to restrain Rho GTPase activity, support Hippo pathway suppressor functions, and restrain prostate cancer migration, invasion, and anchorage-independent growth. This α3β1-Abl kinase-Hippo suppressor pathway identified α3 integrin-deficient prostate cancers as potential candidates for Hippo-targeted therapies currently under development, suggesting new strategies for targeting metastatic prostate cancer based on integrin expression. Our data also revealed paradoxical tumor suppressor functions for Abl kinases in prostate cancer that may help to explain the failure of Abl kinase inhibitor imatinib in prostate cancer clinical trials.

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Integrin α3β1 Can Function to Promote Spontaneous Metastasis and Lung Colonization of Invasive Breast Carcinoma

Cited by 56 publications

References 74 publications

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

A cell–ECM screening method to predict breast cancer metastasis

α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

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