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Clinical Cancer Research 14, 1050, February 15, 2008. doi: 10.1158/1078-0432.CCR-07-4116
© 2008 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

Analysis of Integrin β4 Expression in Human Breast Cancer: Association with Basal-like Tumors and Prognostic Significance

Shaolei Lu1, Karl Simin1, Ashraf Khan2 and Arthur M. Mercurio1

Authors' Affiliations: Departments of 1 Cancer Biology and 2 Pathology, and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts

Requests for reprints: Arthur M. Mercurio, Department of Cancer Biology, University of Massachusetts Medical School, LRB-408, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-8676; Fax: 508-856-1310; E-mail: arthur.mercurio{at}umassmed.edu.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: The β4 integrin has been implicated in functions associated with the genesis and progression of carcinomas based on data obtained from cell lines and mouse models. Data on its expression and relevance to human carcinomas, however, are relatively scant. The aim of this study was to assess its expression and prognostic significance in human breast carcinomas.

Experimental Design: We integrated data on β4 expression from multiple gene profiling studies of breast tumors of known clinical outcome with immunohistochemical analysis of 105 breast carcinomas, and we identified genes whose expression correlates with that of β4.

Results: The expression of both β4 mRNA and protein is not homogeneous in breast cancer and it associates most significantly with the "basal-like" subtype of breast tumors (P = 0.008). No association between β4 and HER2 expression was evident from either gene profiling or immunohistochemical analysis. To gain insight into the relevance of β4 expression to human breast carcinomas, we generated a 65-gene "β4 signature" based on integration of four published gene profiling studies that included the top 0.1% of genes that correlated with β4, either positively or negatively. This β4 signature predicted decreased time to tumor recurrence and survival of patients when applied to four data sets including two independent ones.

Conclusions: These observations indicate that β4 expression in human breast cancer is restricted and associated with basal-like cancers, and they support the hypothesis that β4 may function in concert with a discrete set of proteins to facilitate the aggressive behavior of a subset of tumors.

The {alpha}6β4 integrin (referred to as "β4" because there is only one β4 integrin) is expressed primarily in epithelial cells and in a few other cell types and is defined as an adhesion receptor for most of the known laminins (1). The distinguishing structural feature of β4 is the atypical intracellular domain of the β4 subunit, which is distinct both in size (~1,000 amino acids) and structure from any other integrin subunit (2). A major function of this intracellular domain is to link β4 to intermediate filaments in hemidesmosomes (3). Although the involvement of β4 in hemidesmosome organization and function dominated the study of this integrin, our lab pioneered studies that established that this integrin plays a pivotal role in functions associated with carcinoma progression (4–9), a role that is now widely accepted (3, 10–12). In brief, β4 can regulate key signaling pathways associated with carcinoma progression and facilitate the migration, invasion, and survival of carcinoma cells (3, 13, 14). More recently, β4 has been implicated in the genesis of squamous and breast carcinomas using mouse models (9, 15, 16). A seminal finding is that β4 is mobilized from hemidesmosomes as a consequence of carcinoma progression and it localizes in filamentous actin protrusions where it facilitates migration and invasion and functions as a signaling receptor (6, 10, 14, 17). This dichotomy of β4 function is summarized best by the hypothesis that β4 switches from a mechanical adhesive device into a signaling-competent receptor during the progression from normal epithelium to invasive carcinoma (10, 13).

Given that the data implicating β4 in functions associated with breast and other carcinomas were obtained largely from studies on carcinoma cell lines and some mouse models, a critical issue that needs to be addressed is the relevance of these data to human carcinomas. Surprisingly, relatively few studies have assessed β4 expression in human breast tumors or correlated its expression with clinical outcome. One study that did address this issue using in situ hybridization observed a correlation of β4 mRNA expression with tumor size and grade (18). To gain more insight into this important issue, we integrated data from gene profiling studies of breast tumors of known clinical outcome with immunohistochemical analysis of β4 expression. The results obtained reveal that β4 expression is not homogeneous in breast cancer and that it correlates most significantly with the "basal-like" subtype of breast tumors (19). Moreover, cluster analysis of genes whose expression correlates with β4 generated a β4 "gene signature" that is prognostic for tumor recurrence and decreased survival time.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Tumor samples. A total of 105 cases of invasive ductal breast carcinomas were diagnosed in the Department of Pathology at the University of Massachusetts Medical School from 1997 to 2004. Clinical history and pathology reports on these cases were reviewed to obtain the clinicopathologic information. All of the tumors were invasive ductal cancers. The mean patient age at diagnosis was 59 years (range, 29-94 years); the mean size of the primary tumors was 2.6 cm with a SD of 1.5; 51% of the tumors had local vessel invasion; 59% had local lymph node metastases; 61% had necrotic foci; 47% were estrogen receptor positive (ER+); 61% were progesterone receptor positive (PR+); and 35% were HER2+. All of the slides were reviewed by a pathologist (A.K.) to confirm the diagnosis.

Immunohistochemistry. Two monoclonal integrin β4 antibodies were used [a rat antibody 439-9b from Dr. Rita Falcioni, (Regina Elena Cancer Institute, Rome, Italy) and a mouse antibody Elf-1 from Novocastra]. The 439-9b antibody was used at a final concentration of 2 µg/mL and Elf-1 antibody was used at 1:50 dilution. The paraffin-embedded cancer sections were stained using corresponding streptavidin-biotin systems (Vectastain Elite avidin-biotin complex kit, Vector Laboratories). Antigen retrieval was done by steaming the slides for 30 min in a citrate buffer (pH 6.0; Zymed/Invitrogen). Endogenous peroxidase was quenched by 3% hydrogen peroxide (Sigma-Aldrich). Endogenous biotin was blocked using the avidin/biotin blocking system (Vector Laboratories), and casein (Vector Laboratories) was used to diminish nonspecific staining. In addition, keratin 5/6 immunostaining was done on all tumors using a mouse monoclonal antibody from DakoCytomation at 1:50 dilution and pretreatment with EDTA at pH 8.0. Horseradish peroxidase was developed using 3,3'-diaminobenzidine tetrahydrochloride (DakoCytomation), and the specimens were counterstained with hematoxylin.

Statistical analysis. The Student's t test was used to compare integrin β4 gene expression levels in tumor subtypes whose data were extracted from the molecular portraits data (19) and the combined data set (20). Pearson correlation was used to correlate integrin β4 with keratin 5 and HER2 expression in tumors. {chi}2 analysis was used to assess the associations between integrin β4 and other characteristics. The survival curves were estimated and compared using Kaplan-Meier estimates and log-rank test. All P values were two sided and P values of <0.05 were considered statistically significant. These analyses were carried out using JMP 6.0 (SAS Institute).

Generation of integrin β4 gene signature gene. Four breast cancer gene profiling data sets (19–22) were reanalyzed using GeneSpring GX 7.3.1 (Agilent Technologies). Pearson correlations between integrin β4 and other genes in these data sets were calculated and ranked. The top 0.1% of genes that correlated positively and the bottom 0.1% of genes that correlated negatively with β4 were collected, and 65 β4 signature genes were identified that are common to at least two data sets (Table 3). Other β4-related genes that are present in only one data set are listed in Supplementary Table S1.


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  		Table 3. List of 65 β4 signature genes

 
To classify tumors based on β4 gene signature, expression data of these genes were extracted from published data sets and tumors were clustered hierarchically by Cluster 3.0 (23) in an unsupervised way (centered average linkage). Java TreeView (24) was used to display the dendrogram and to identify tumors that exhibited high and low expression of the β4 signature based on the first two branches of tumor clustering. The survival analyses were then done to compare the clinical outcome of these two tumor groups.


   Results
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 Materials and Methods
 Results
Discussion
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Analysis of gene profiling data reveals that β4 is associated with basal-like breast cancers. In the original study on the molecular portraits of breast cancer molecular profiling, breast cancers are classified into four subsets, including basal-like and luminal tumors, and β4 was identified in one of the two basal gene clusters (19). We reanalyzed the original data and found that β4 expression in both probe sets is significantly higher in basal-like tumors than it is in luminal tumors (both P < 0.0001; Fig. 1A and C ). A more recent analysis that fused three independent microarray studies into a single data set identified β4 as one of 306 "intrinsic" genes that are common to all three microarray studies and that can be used to classify breast tumor subtypes (luminal A and B, and basal like; ref. 20). We compared β4 expression levels among these different tumor subtypes and observed once more that β4 expression in basal-like tumors is significantly higher than it is in the luminal subtypes (both P < 0.0001; Fig. 1E).


Figure 1
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  		Fig. 1. Analysis of β4 expression in two gene profiling data sets of breast cancer. A and C, β4 expression in basal-like and luminal tumors based on the data from two probe sets of the molecular portraits data (19). B and D, regression analysis assessing the relationship between β4 and keratin 5 (KRT5), and β4 and HER2 expression using the molecular portraits data. There are two, three, and four probe sets representing β4, keratin 5, and HER2 expression, respectively. E, β4 levels in basal-like and luminal tumors of the combined data set (20). F, regression analysis of integrin β4 and HER2 expression in the combined data set. *, significant difference (P < 0.0001). The values at the X-axis and Y-axis are normalized gene expression data. The top and bottom boundaries of the boxes indicate mean (±SE). The mean is denoted by a horizontal line in the box. The whiskers above and below extend to mean (±SD).

 
Basal-like tumors are characterized by their expression of basal keratins, including keratins 5, 6, and 14 (25). We calculated the correlation between β4 and keratin 5 expression in the molecular portraits data. In a set of six Pearson correlation studies based on two β4 probes and three keratin 5 probes (Fig. 1B and D, top), there is a clear positive association between β4 and keratin 5 expression (R2 values range from 0.18 to 0.32).

Studies using breast cancer cell lines and mouse models have shown both a physical and functional association between β4 and erbB2 (HER2) expression (16, 26, 27). One inference of these data is that the expression of these two receptors correlates in human breast tumors. Surprisingly, however, there is no correlation in their expression based on data from two β4 probes and four HER2 probes with R2 values ranging from 0.01 to 0.08 (Fig. 1B and D, bottom). In addition, regression analysis of the data retrieved from the combined data set of 315 tumors substantiated a lack of correlation between β4 and HER2 (R2 = 0.0245; Fig. 1F).

Immunohistochemical analysis of β4 expression confirms an association with basal-like tumors. To validate our analysis of β4 gene expression and confirm that β4 is associated with basal-like tumors, we assessed β4 protein expression in 105 cases of primary invasive ductal breast cancers by immunohistochemistry. Data on the expression of the ER, PR, HER2, and cytokeratin 5/6 were available for all of these tumors. Two different β4 monoclonal antibodies (Elf-1 and 439-9b) were used for the immunohistochemistry that yielded similar staining patterns. Both monoclonal antibodies stained the basal layer of skin intensely, as well as the myoepithelium of normal mammary gland (Supplementary Fig. S1). Interestingly, only 32% (34 of 105) of the tumors exhibited β4 staining that was predominantly localized to the cell surface and seen in discrete clusters of cells within tumors (Fig. 2A and B ). Some tumors (6 of 34) exhibited additional cytosolic β4 staining (Fig. 2C). We noted that cytokeratin 5/6–positive basal-like tumor cells tended to express β4 (Fig. 2D and E), and β4 expression was evident in areas of squamous metaplasia (Fig. 2F), which is also classified as basal like (28).


Figure 2
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  		Fig. 2. Integrin β4 staining patterns in breast cancer. A, cell surface staining pattern. B, epithelial-stroma boundary pattern. C, mixed cell surface and cytosolic pattern. D and E, coexpression of β4 (D) and basal keratin 5/6 (E) in an invasive ductal cancer. F, β4 expression in a squamous metaplastic cancer.

 
Analysis of the immunohistochemical data revealed an inverse association between β4 expression and both ER (P = 0.006) and PR (P = 0.009) and no association between β4 and HER2 (P = 0.511; Table 1 ). In contrast, a significant association between β4 and ER–, PR–, and HER2– (triple negative) tumors was evident (P = 0.008). A significant association also exists between β4 and cytokeratin 5/6 expression (P = 0.026). Collectively, these data indicate that β4 expression is associated with a basal-like phenotype, a finding that substantiates the gene expression analysis described above. We also classified these tumors into four subtypes (luminal A, luminal B, HER2+/ER–, and basal like) based on the immunohistochemical criteria established by Carey et al. (29). This analysis also revealed a significant correlation between β4 and the basal-like subtype but not with the luminal A and luminal B subtypes (Table 2 ). A link between β4 and the HER2+/ER– subtype could not be established because there were only six such tumors.


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  		Table 1. Integrin β4 is associated with basal-like features

 

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  		Table 2. Integrin β4 is associated with basal-like tumors

 
Integrin β4 signature genes are associated with poor prognosis. To test the relationship between clinical outcome and the expression of genes highly correlated with β4, four independent gene profiling data sets were analyzed (19, 21, 22, 30). This analysis is based on the hypothesis that genes whose expression correlates significantly may function in common mechanisms to affect tumor behavior. Using Pearson correlations, a 65-gene "β4 signature" was generated that is composed of the top 0.1% of genes that correlate either positively or negatively with β4 in at least two of the four data sets (Fig. 3A ; Table 3 ). Genes that correlated in only one data set are listed in Supplementary Table S1.


Figure 3
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  		Fig. 3. Integrin β4 signature genes predict clinical outcomes. A, classification of 295 breast tumors of Chang et al. (30) by 65-gene β4 signature. B and C, Kaplan-Meier relapse-free and overall survival curves showing the outcomes of β4 signature–high and β4 signature–low groups from the 295 tumors. D, overall survival curves of β4 signature–high and β4 signature–low groups from a total of 162 tumors of Korkola et al. (21). E, relapse-free curves of β4 signature–high and β4 signature–low groups from a total of 99 tumors of Sotiriou et al. (31). F and G, relapse-free and overall curves of two β4 signature–high and β4 signature–low groups from a total of 106 tumors from the University of North Carolina Microarray Database.

 
To test the prognostic power of the β4 signature, the expression data of the 65 signature genes were used to cluster 295 breast cancer samples from Chang et al. (Fig. 3A; ref. 30). The two groups defined by the first branch of the dendrogram were designated as "β4-high" and "β4-low" expressing tumors. Comparison of the Kaplan-Meier survival curves showed that β4-high tumors had worse relapse-free survival (P = 0.0229) and overall survival (P = 0.0447) than did β4-low tumors (Fig. 3B and C).

We next analyzed three other data sets of available clinical data: one that was used to generate the signature (21), one independent data set from Sotiriou et al. (31), and another independent 106-tumor data set from the University of North Carolina Microarray Database.3 The integrin β4 signature in all data sets divided tumor samples into two groups of distinct outcome. High expression of the β4 signature predicts significantly decreased overall survival compared with low expression in 162 tumors from Korkola et al. (P = 0.0008; Fig. 3D; ref. 21). The β4 signature also predicted the clinical outcome of 99 tumors from Sotiriou et al. (P = 0.0336; Fig. 3E; ref. 31) and 106 tumors from the University of North Carolina with respect to relapse-free survival (P = 0.0818) and overall survival (P = 0.0296; Fig. 3F and G).


   Discussion
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 Materials and Methods
 Results
 Discussion
References
 
Although the β4 integrin has been implicated in the genesis and progression of carcinomas based on data from cell lines and mouse models (reviewed in refs. 3, 13, 14), data on its relationship to the clinical properties of human carcinomas are relatively scant, although interesting data exist on the correlation between β4 mRNA expression and breast tumor size and grade (18). In general, however, existing assumptions on β4 expression in carcinomas are rather generic in this regard: β4 expression can be maintained (e.g., breast and squamous), increased (e.g., thyroid), or suppressed (e.g., prostate) during the progression from normal epithelium to carcinoma (reviewed in ref. 32). For the most part, such studies have not considered the complex pathology of specific carcinomas or a potential association of β4 with clinical outcome. Using a two-pronged approach that involved analysis of gene profiling data from human breast tumors and immunohistochemical analysis of these tumors, we determined that β4 expression is not homogeneous in breast cancer but that its expression is restricted to a limited number of tumors and correlates most significantly with basal-like tumors. Moreover, we identified a cluster of genes whose expression correlates with that of β4 in four gene profiling data sets of breast tumors. The value of this β4 signature is that it can predict clinical outcome when applied to independent data sets of human breast tumors. Importantly, the hypothesis that can be derived from these findings is that the genes present in the β4 signature function in concert with β4 to affect tumor behavior and affect the clinical progression of human breast cancer.

A major finding in this study is that both β4 gene and protein expression correlates most significantly with basal-like tumors. These are aggressive tumors identified initially by gene profiling that account for 15% to 30% of all breast cancers (33). These tumors express basal cytokeratins and other basal markers but often lack expression of the ER, PR, and HER2. As a consequence, they are refractory to tamoxifen and Herceptin therapy. The association of β4 expression with basal-like tumors is consistent with the fact that β4 is expressed in the basal myoepithelial cells of the normal mammary gland. Most, if not all, breast tumors that contain inactivating mutations in the BRCA1 gene, which is a major determinant of hereditary breast cancer, exhibit a basal phenotype (34). Interestingly, the frequency of basal phenotype breast carcinomas in premenopausal African-American women is twice that for Caucasian women and this statistic may contribute to the fact that these women have a 77% higher mortality from breast cancer than do Caucasian women (29). An important issue that arises from these findings is the functional role of β4 in basal-like tumors. This issue should be amenable to analysis using transgenic mouse models because such models have been described recently for basal-like tumors (35). Although our data reveal a significant correlation between β4 expression and the basal phenotype, they also indicate that there are some β4-positive tumors that are not basal like and a smaller number of basal-like tumors that are β4 negative (Table 2). It will be informative to assess the prognosis of patients with such tumors as a function of β4 expression.

The relationship between β4 and erbB2 merits discussion based on our findings and previously published data. Compelling data, which were obtained using breast carcinoma cell lines, showed a physical association between β4 and erbB2 on the cell surface and established that these two receptors can cooperate to activate phosphatidylinositol 3-kinase and promote β4-dependent invasion (26, 27). More recently, a mouse model of mammary carcinoma was used to investigate the role of β4 in breast cancer and its relationship to erbB2 (16). For this purpose, mice that express a constitutively active erbB2 in the mammary gland that results in mammary carcinogenesis (MMTV-neu) were crossed with mice that express a cytoplasmic domain deletion of the β4 integrin subunit that is purported to be signaling deficient. The major finding in this study was that deletion of the β4 cytoplasmic domain impeded MMTV-neu–driven tumorigenesis and invasive growth, and it was inferred that β4 is a potential target for breast tumors with amplified expression of erbB2. Our finding, however, that the expression of β4 does not correlate with that of erbB2 in human breast tumors questions the relevance of this bigenic mouse model to HER2+ human breast cancer. Aside from our findings, the fact that β4 was linked to basal-like tumors in the original profiling studies of human breast cancer diminishes the therapeutic potential of β4 and erbB2 because such tumors are defined by their lack or minimal expression of HER2 (19). It should be noted, however, that the epidermal growth factor receptor (erbB1) is a basal marker in breast cancer (19) and its expression clusters with that of β4 (Table 3). These observations are of interest in light of the studies that have shown a functional cross-talk between epidermal growth factor receptor and β4 that may facilitate carcinoma progression (17, 36, 37). For these reasons, targeted therapies aimed at both epidermal growth factor receptor and β4 may prove effective for some types of breast cancer.

The most novel aspect of this study is the generation of the β4 gene signature that is prognostic for reduced survival and tumor recurrence. The hypothesis that derives from this cluster analysis is that genes whose expression correlates significantly with β4 may function in common mechanisms to affect tumor behavior. This hypothesis is supported by strong evidence from the analysis of gene expression in yeast and emerging data in mammalian cells (23). The β4 signature (Table 3), as well as the β4-related gene list (Supplementary Table S1), includes known markers of basal-like breast cancers, such as K5 and K14 (38), Sox9 (19), P-cadherin (39), laminin (40), fascin (40), epidermal growth factor receptor (41), and Annexin A8 (42), and genes that are expressed primarily in basal myoepithelial cells of the mammary gland, such as WT-1 (43) and S100A2 (Table 3; Supplementary Table S1; ref. 44). Some of these gene products have been shown to have prognostic value for breast cancer, such as WT-1 (43) and P-cadherin (39), but others need to be evaluated more rigorously, and all of these genes need to be evaluated within the context of β4 function. It merits mentioning in this context that previous studies on squamous cell carcinomas linked β4 to poor clinical outcome and found that its expression associated with some of the basal markers that we identified in our β4 signature, including {alpha}3 integrin and laminin (45, 46). Indeed, these earlier studies provided the first evidence that β4 expression could be correlated with clinical outcome and they identified a "suprabasal" phenotype for squamous cell carcinomas.

The fact that the β4 signature contains actin-binding proteins (filamin A and fascin) is intriguing in this regard because these proteins share in common with β4 the ability to facilitate the formation and stabilization of actin protrusions and actin-membrane interactions that mediate cell migration and invasion (47, 48). Fascin is of particular interest in this regard because its expression in breast cancer is associated with basal-like tumors (49). Sox9 also merits further investigation because it exhibits a strong correlation with β4 in the molecular portraits data (19), has been implicated in the maintenance of a basal/progenitor cell population in other epithelia (50, 51), and is associated with recurrent prostate cancer (51). At the very least, the β4 gene signature provides a wealth of information for investigating functional interactions that may contribute to the aggressive behavior of a subset of human breast tumors. The β4 signature could also affect our understanding and treatment of basal-like breast tumors. The biology of these tumors is not well understood and there is a need to identify novel and specific therapeutic targets because current treatment modalities are limited. Defining the functional roles of these basal markers in breast cancer and assessing their relationship to β4 will facilitate our understanding of basal-like tumors and the design and development of therapeutic approaches for these aggressive tumors.


   Acknowledgments
 
We thank Dr. Rita Falcioni for providing the β4 antibody, Dr. Chung-Cheng Hsieh for review of the statistical analysis, and Karen Dresser for technical assistance.


   Footnotes
 
Grant support: NIH grant CA80789 and Susan G. Komen Breast Cancer Foundation grant PDF0600265.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

3 http://genome.unc.edu/pubsup/breastGEO/ Back

Received 9/ 4/07; revised 10/26/07; accepted 10/29/07.


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