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Clinical Cancer Research Vol. 6, 2417-2423, June 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Immunohistochemical Analyses of Focal Adhesion Kinase Expression in Benign and Malignant Human Breast and Colon Tissues: Correlation with Preinvasive and Invasive Phenotypes1

William G. Cance2, Janet E. Harris, Mary V. Iacocca, Elizabeth Roche, XiHui Yang, Jinli Chang, Stephen Simkins and LiHui Xu

Departments of Surgery [W. G. C., J. E. H., E. R., X. Y., J. C., L. X.] and Pathology [M. V. I.] and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7210, and Department of Microbiology, Pathology, and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27695 [S. S.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The focal adhesion kinase (FAK) is a protein tyrosine kinase linked to signaling events between cells and the extracellular matrix. Studies at the Western blot level have demonstrated up-regulation of FAK expression in invasive breast and colon cancers. To assess p125FAK expression at the cellular level, we developed monoclonal antibodies that specifically detected FAK in formalin-fixed, paraffin-embedded tissue sections and analyzed the levels of FAK expression in human breast and colon tissues. Monoclonal antibody 4.47 demonstrated FAK-specific focal adhesion staining by immunofluorescence assays on BT-474 breast cancer cells and detected a Mr 125,000 protein by both Western blotting and immunoprecipitation analyses. Using immunohistochemical techniques, the expression of p125FAK was analyzed in 36 normal and 43 preinvasive or invasive human breast and colon tissues from individual patients. FAK was weakly expressed in most benign breast epithelium but was up-regulated at moderate or strong levels in 14 of 18 invasive breast carcinomas. In seven samples of ductal carcinoma-in situ, FAK was overexpressed. Borderline-to-weak expression of FAK was detected in the normal colonic epithelium. In the invasive colon cancers, FAK was overexpressed at moderate or strong levels in 13 of 15 tumors. Furthermore, FAK expression was up-regulated in areas of dysplastic, premalignant colon epithelium. These results provide the first evidence at the cellular level that FAK expression is variably overexpressed in breast and colon cancer and suggest that up-regulation occurs at an early stage of tumorigenesis.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The FAK3 is a protein tyrosine kinase that is a critical mediator of signaling events between cells and their extracellular matrix. Originally identified in v-src-transformed chick embryo fibroblasts (1) , FAK has been linked to integrin-signaling pathways (2, 3, 4, 5) , cellular motility (6) , and apoptosis (7, 8, 9) . FAK not only functions as a kinase but also serves as a scaffolding protein for the recruitment of other Src-homology 2 (SH2) and Src-homology 3 (SH3)-containing signaling molecules (10) . In tumor cells, FAK is thought to have a dual function both in promoting tumor cell adhesion and in acting as a survival signal to inhibit apoptosis as a tumor develops anchorage-independent growth properties.4

Although several studies have demonstrated up-regulation of FAK expression as normal breast and colon tissues become transformed and develop into primary, invasive carcinomas (11, 12, 13, 14) , the significance of these findings has remained controversial (15) . Some studies, in fact, have not demonstrated p125FAK overexpression in human breast cancer cells (16) . Thus, the significance of FAK expression in human tumors remains to be determined. Many of the analyses have relied largely on blotting methods to demonstrate mRNA and p125FAK overexpression, with the inherent problems of being unable to distinguish tumor cells from surrounding stromal contaminants. In addition, blotting techniques do not allow the comparison of FAK expression at the cellular level between preinvasive lesions, such as DCIS or dysplastic colon polyp epithelium and invasive carcinoma.

Most of the available anti-FAK antibodies are unsuitable for large studies of p125FAK expression in human tumors because they do not readily detect p125FAK on FFPE tissue sections. For example, our polyclonal V39 anti-FAK antibody specifically recognized p125FAK on Western blots but was not a suitable reagent for immunohistochemistry. For these reasons, we have developed monoclonal antibodies against the NH2 terminus of FAK that recognize p125FAK by immunohistochemical analyses of FFPE specimens. This has allowed us to directly compare the levels of FAK expression between benign and malignant cells. In this report, we have characterized the expression of p125FAK in matched samples of normal and malignant breast and colon tissues from individual patients and have demonstrated, for the first time at the immunohistochemical level, up-regulation of p125FAK in both preinvasive and invasive breast and colon cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Development of Anti-p125FAK Monoclonal Antibody 4.47.
To develop a FAK-specific monoclonal antibody, we developed an immunogen directed at the NH2 terminus of the molecule to avoid consensus sequences within the kinase domain as well as cross-reactivity with the autonomously expressed COOH-terminal fragment of FAK, FRNK (17) . We created a GST fusion protein containing amino acids 1–423 of FAK, immunized mice, and we performed fusions according to standard techniques (18) . A total of 1600 supernatant samples were initially screened by ELISA for FAK immunoreactivity. Positive clones were then screened by indirect immunofluorescence assays on BT-474 breast cancer cells as described below. Finally, clones were analyzed by immunohistochemistry on FFPE tissue sections, as described below. We created three FAK-specific monoclonal antibodies, two of which recognized p125FAK on FFPE sections. In this report, we have focused on monoclonal antibody 4.47 (available from Upstate Biotechnology, Inc., Lake Placid, NY).

Immunofluorescence, Western Blotting, and Immunoprecipitation Analyses.
Indirect immunofluorescence microscopy was performed on BT-474 breast cancer cells using standard techniques (19) . FAK -/- knockout embryo fibroblasts (kindly provided by Steven Hanks, Vanderbilt University, Nashville, TN) were used as a negative control in these assays to demonstrate p125FAK specificity. Lysates of paired normal and tumor samples were prepared as described (12) , and 50 µg of cell lysate were analyzed for FAK expression by Western blotting using anti-FAK 4.47 monoclonal antibody (1:50 dilution; 0.3 µg).

For immunoprecipitation, 500 µg of tissue lysate were incubated with 10 µg of anti-FAK 4.47 monoclonal antibody in the presence of protein G plus protein A agarose (Calbiochem, San Diego, CA). The precipitated proteins were resolved on SDS-PAGE and immunoblotted using the anti-FAK 4.47 monoclonal antibody or anti- FAK polyclonal antibody (C20; Santa Cruz Biotechnology, Santa Cruz, CA). Proteins were visualized using the enhanced chemiluminescence detection system (Amersham, Arlington Heights, IL; Ref. 20 ).

Tissue Samples and Immunohistochemistry Assays.
Fresh frozen as well as FFPE breast and colon tissue samples were obtained from University of North Carolina-Lineberger Comprehensive Cancer Center Tissue Procurement and Analysis Facility as well as the University of North Carolina Department of Pathology. FFPE tissue was obtained from 21 patients with breast carcinoma, 2 patients with villoglandular polyps of the colon, and 15 patients with colon carcinoma. All of the H&E-stained sections were reviewed, and areas of benign epithelium, dysplasia within polyps, and colon and breast carcinoma were identified. Paired normal and neoplastic/tumor samples were examined in 36 of these patients.

Immunohistochemistry was performed as described previously (21) , with the following modifications. After deparafinization, rehydration, and quenching of endogenous peroxidase activity, mercuric pigments were removed by incubating sections in Auto/Iodine (Fischer Scientific, Pittsburgh, PA) for 1 min. Slides were incubated in Redusol (Fischer Scientific) two times for 2 min. each. The hydration process was completed by rinsing three times for 3 min in 1x Automation Buffer (Fischer Scientific).

Heat-induced epitope recovery was used as sections were submerged in 200 ml of 1x Antigen Retrieval Citra Buffer (Biogenex) and steam-heated in a standard steamer (Black and Decker) for 30 min. Sections were blocked in normal horse serum for 15 min and then incubated with anti-FAK 4.47 monoclonal antibody (1:50 dilution; 0.3 µg) overnight at 4°C. Control sections were incubated with a comparable concentration (1:37; 0.3 µg) of isotype-matched monoclonal antibody, MOPC-21 (Sigma, St. Louis, MO).

The sections were washed extensively in Automation Buffer and then incubated with biotinylated goat antimouse IgG followed by avidin peroxidase using the Vectastatin ABC elite kit (Vector Laboratories, Burlingame, CA). The chromogenic reaction was performed with DAB, toned with the DAB enhancing solution (Vector Laboratories).

Immunohistochemistry Scoring.
A single pathologist (M. V. I. ) scored each tissue section for FAK expression. Epithelium from each section was scored for staining intensity based on the following scoring system: 0, none; 1+, borderline; 2+, weak; 3+, moderate; 4+, strong. Staining characteristics of cellular localization (cytoplasm, nucleus, membrane, combination thereof) and overall distribution (homogeneous throughout cell population, unifocal, heterogeneous, or multifocal) were recorded.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characterization of Anti-p125FAK Monoclonal Antibody 4.47.
To demonstrate immunoreactivity of this monoclonal antibody at the focal adhesions, indirect immunofluorescence assays were performed on BT-474 breast cancer cells. Monoclonal antibody 4.47 localized p125FAK specifically to the focal adhesions of these cells (Fig. 1A)Citation . In contrast, staining of the FAK-/- knockout embryo fibroblasts with this antibody did not detect specific localization of p125FAK at the focal adhesions (Fig. 1A)Citation , although these cells demonstrated intact focal adhesions when probed for the focal adhesion protein, paxillin Citation . In addition, staining BT-474 cells with the antibody preincubated with GST-FAK-NH2 terminal immunogen (data not shown) abrogated the specific localization of p125FAK, further suggesting the specific immunoreactivity of the antibody.



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  		Fig. 1. Characterization of monoclonal antibody 4.47 for specific p125FAK immunoreactivity. A, left, indirect immunofluorescence on BT-474 breast cancer cells demonstrates intense staining at focal adhesions; middle, the FAK -/- knockout fibroblasts demonstrate no focal adhesion staining with 4.47, despite having intact focal adhesions by paxillin staining (right), thus demonstrating the specificity of the antibody. B, Western blot analyses comparing antibodies 4.47 and C20 on lysates of RD rhabdomyosarcoma cells, BT-474 cells, and FAK-/- fibroblasts. An intense Mr 125,000 band is demonstrated in the RD and BT-474 cells, with no reactivity in the FAK knockout fibroblasts. C, immunoprecipitation analyses demonstrating that antibody 4.47 immunoprecipitates a Mr 125,000 protein from a RD cell lysate, detected by both 4.47 and C20. The murine IgG heavy chain (IgGHC) is seen in the 4.47 lane.

 
To determine whether the 4.47 antibody recognized the Mr 125,000 FAK protein in other confirmations, western blot and immunoprecipitation analyses were performed using the RD rhabdomyosarcoma cell lysate. Western blot analyses were performed as described below, detecting a Mr 125,000 protein that comigrated with the p125FAK detected by using a commercially available anti-FAK polyclonal antibody, C20 (Fig. 1B)Citation . Immunoprecipitation analyses demonstrated that this 4.47 monoclonal antibody specifically recognized p125FAK in a native confirmation (Fig. 1C)Citation as compared with the anti-FAK C20 antibody. The specificity of 4.47 antibody was further demonstrated by blocking studies where immunoblotting or immunoprecipitation was abrogated when the antibody was preincubated with the GST-FAK-NH2 terminal immunogen (data not shown).

p125FAK Is Overexpressed in Noninvasive DCIS and Invasive Breast Cancer.
In the 20 samples of benign breast epithelium that were obtained from patients with breast cancer, there was little detectable p125FAK expression (Table 1)Citation . Eight patients had no detectable FAK expression in their benign ducts and lobules, and 9 patients had only borderline-to-weak expression. Only three samples demonstrated moderate or strong FAK immunoreactivity in the benign epithelium. Intriguingly, the benign ducts and lobules adjacent to a site of DCIS or invasive carcinoma frequently demonstrated p125FAK immunoreactivity, whereas the benign tissue remote from the cancer usually had minimal to undetectable FAK expression. In contrast, p125FAK was detected at varying levels in all of the breast carcinoma specimens from the 21 patients that we tested. The significant up-regulation of FAK expression in these breast cancer tissues is demonstrated in the benign breast tissue and infiltrating ductal carcinoma from patient 4 (Fig. 2A)Citation . Here, a benign breast lobule (Fig. 2ACitation , NOR) lacks significant FAK expression, whereas the carcinoma (Citation , INV) demonstrates strong (4+) FAK expression in both the cytoplasm and the cytoplasmic membrane of the tumor cells. The intensity of FAK expression in the malignant, invasive epithelium ranged from 1+ to 4+, with 14 of the 18 samples expressing moderate or strong (3+ or 4+) FAK immunoreactivity. However, not the entire population of tumor cells in these specimens overexpressed p125FAK. As noted in Table 1Citation , there was a variability in percentage of tumor cells demonstrating immunoreactivity against FAK, ranging from 5 to 100% of the tumor cells.


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  		Table 1 Immunohistochemical analyses of p125FAK expression in breast epithelium: benign, DCIS, and invasive cancer

 


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  		Fig. 2. FAK overexpression in invasive human breast cancer and DCIS. A, paired samples of normal breast (NOR) and invasive breast cancer (INV) from the same patient demonstrate no detectable FAK expression in the normal tissue. In contrast, the invasive breast cancer cells (INV) demonstrate intense membrane and cytoplasmic immunoreactivity for p125FAK. Note the absence of immunoreactivity in the surrounding tumor-infiltrating lymphocytes (immunohistochemistry, x600). B, in this single FFPE tissue section, the focus of DCIS (DCIS) expresses p125FAK at a slightly lower level than the adjacent focus of infiltrating ductal carcinoma (INV; left; x200). These two areas are shown at higher magnification (x600) to demonstrate this difference (DCIS, middle; INV, right).

 
The invasive breast carcinoma specimens represented a variety of cell types, including pure invasive ductal, mixed ductal and lobular, and pure invasive lobular carcinomas. In addition, seven of the samples contained DCIS either by itself (patients 12, 13, and 14), or adjacent to an infiltrating carcinoma (patients 16, 17, 18, and 19). Intriguingly, each of these DCIS samples demonstrated intense FAK overexpression, comparable with their invasive counterparts. This is shown in a tissue section from patient 18 (Fig. 2B)Citation , where the DCIS (Fig. 2BCitation , DCIS) and the invasive carcinoma (Citation , INV) both show 3+ staining intensity in 90% of cells. These results suggest that overexpression of FAK is an early event in breast carcinoma and is not restricted to fully invasive tumors.

p125FAK Is Overexpressed in Preinvasive Dysplastic Colon Epithelium and Invasive Colon Cancers.
The 16 benign colon samples that we studied represented the paired samples of normal colon mucosa from patients with dysplastic colon polyps or invasive colon cancer (Table 2)Citation . In these normal tissues, we detected low levels of FAK expression in 13 of the specimens, consistent with the ongoing proliferative and migratory events of normal colonic epithelial cells. Even so, the p125FAK expression in these normal cells was borderline to weak (1+ to 2+) in 12 of the tissues, with only 1 demonstrating moderate FAK expression. Furthermore, these low levels of p125FAK were detected in only 25% or less of the normal colon epithelial cells.


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  		Table 2 Immunohistochemical analyses of p125FAK expression in colon epithelium: benign, dysplastic, and malignant

 
In contrast, p125FAK was markedly up-regulated in the invasive colon carcinomas, regardless of baseline (benign) expression (Table 2)Citation . Thirteen of the 15 invasive tumors had moderate or strong (3+ or 4+) levels of p125FAK expression, and 10 of these 15 tumors expressed p125FAK in 75% or more of their tumor cells. To illustrate these results, the colon carcinoma from patient 8 demonstrated strong (4+) FAK expression in approximately 90% of the cells (Fig. 3ACitation , INV), whereas the benign, normal epithelium had little detectable p125FAK reactivity (Fig. 3ACitation , NOR). Two of the carcinomas expressed only borderline p125FAK in 10% of tumor cells (patients 3 and 13), which demonstrated that there was some variability between individual tumors.



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  		Fig. 3. FAK overexpression in invasive human colon cancer and colon dysplasia. A, this paired sample of normal colon (NOR) and invasive colon cancer (INV) from the same patient demonstrates little detectable p125FAK immunoreactivity in the normal colon mucosa. In contrast, the invasive colon cancer demonstrates intense FAK immunostaining in the cytoplasm of the tumor cells (immunohistochemistry, x400). B, this individual FFPE section demonstrates normal colon mucosa (NOR), with adjacent dysplastic mucosa (DYS), surrounded by a colon cancer that has invaded underneath the normal mucosa (INV; x200). Inset in the left panel, the junction between normal and invasive tumor, which is shown at a higher magnification (x600) in the right panel, demonstrates the difference in levels of p125FAK expression.

 
Two of the tissue samples represented large villoglandular polyps obtained from operative specimens (patients 1 and 2). One of these noninvasive, dysplastic colon tissues overexpressed p125FAK with 4+ intensity in 80% of cells, whereas the other showed 2+ intensity in 50% of the cells (Table 2)Citation . The overexpression of p125FAK in dysplastic colonic epithelium is further shown in Fig. 3BCitation , in which the tissue section demonstrates the junction between nondysplastic colon epithelium (Citation , NOR) and dysplasia (Fig. 3BCitation , DYS) with an underlying invasive adenocarcinoma (Fig. 3BCitation , INV) in patient 14. Both the dysplastic and the malignant, invasive epithelium stained with 3+ intensity, whereas the benign epithelium demonstrated focal FAK expression of 1+ intensity in 10% of cells. Thus, similar to the results in the noninvasive breast tissues, the premalignant, dysplastic colon epithelia seemed to overexpress FAK before acquiring the fully malignant and invasive phenotypes.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These results provide definitive evidence, at the cellular level, that the expression of p125FAK is up-regulated as normal breast and colon tissues undergo malignant transformation. The levels of FAK overexpression in breast and colon tumor cells represent a higher degree of overexpression than some of the other tyrosine kinases known to be overexpressed in human tumors, such as Src in colon cancer (22 , 23) . Furthermore, the results demonstrate that FAK overexpression seems to be an early event in the development of breast and colon cancer, occurring in some tissues before the tumor has acquired its full invasive potential.

It is intriguing to speculate on possible reasons for these high levels of FAK overexpression during tumorigenesis. FAK has been shown to be a survival signal for anchorage-dependent cells (8 , 24) , and inhibition of FAK expression in tumor cells has been shown to result in cell death (7 , 19) . Thus, it is conceivable that tumor cells up-regulate FAK expression to maintain survival as they progress through the anchorage-dependent and anchorage-independent phases of growth, invasion, and metastasis.

In this study, we have examined paired samples of normal and neoplastic tissues from individual patients. This has given us the advantage of directly comparing levels of FAK expression within the same genetic background. In addition, the individual tissue sections that contained a combination of normal, preinvasive, and invasive breast and colon tissues have allowed us to compare FAK expression in these pathological types without the potential variability of immunostaining between different slides. As a caveat to these results, it has been shown that molecular genetic aberrations occur in normal ducts adjacent to breast cancers (25) . This raises the possibility that the noninvasive lesions adjacent to the invasive cancers may contain such genetic abnormalities that could have an influence on FAK expression. Indeed, in benign ducts and lobules adjacent to tumors, up-regulation of FAK expression was seen.

The inconsistency of studies examining the levels of FAK expression in human tumors may, in part, be explained by problems with existing antibodies recognizing p125FAK on FFPE tissue sections. Although some investigators have been able to use the prototype anti-FAK 2A7 antibody (26) in immunohistochemical analyses (27) , other investigators have not seen comparable results, which leads to conclusions that p125FAK is not up-regulated in breast tumor cells (16) . Notably, the 2A7 antibody was raised against avian FAK bound to Src in an immunoprecipitate, in contrast to 4.47, which was raised specifically against human FAK. Furthermore, 2A7 recognizes a COOH-terminal epitope in both FAK and FRNK, whereas 4.47 recognizes a FAK-specific epitope in the NH2 terminus. We have not had reproducible success using 2A7 or other commercially available monoclonal antibodies for immunohistochemical analyses (data not shown) and, thus, have sought to produce monoclonal antibodies against p125FAK that were suitable for FFPE analyses. The development of this immunohistochemical reagent, antibody 4.47, will allow large studies of FAK expression in population-based archival samples to be performed to determine whether there is diagnostic and prognostic significance to the levels of p125FAK expression.

In summary, these results are the first definitive immunohistochemical evidence that FAK expression is up-regulated in breast and colon cancer. The 4.47 antibody can be used to study FAK in other tumor systems to determine whether these correlations are, in fact, common among different types of tumors. Finally, this dramatic up-regulation of FAK in tumors, combined with the relative lack of expression in normal breast and colon tissues, suggests that FAK is a rational target for breast and colon cancer therapeutics.


   ACKNOWLEDGMENTS
 
We thank Lynn Dressler, David Cowan, and the Tissue Procurement and Analysis Core Facility of the University of North Carolina Lineberger Comprehensive Cancer Center for immunohistochemistry advice and tissue specimens. We thank Rolf Craven and Shelton Earp for critical review of the manuscript.


   FOOTNOTES
 
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.

1 Supported by National Cancer Institute Grant CA65910. W. G. C. is a recipient of the George H. A. Clowes, Jr., Memorial Research Career Development Award from the American College of Surgeons. Back

2 To whom requests for reprints should be addressed, at University of North Carolina at Chapel Hill, Department of Surgery, CB No. 7210, Chapel Hill, NC 27599-7210. Phone: (919) 966-5221; Fax: (919) 966-8806; E-mail: cance{at}med.unc.edu Back

3 The abbreviations used are: FAK, focal adhesion kinase; FRNK, FAK-related nonkinase; FFPE, formalin-fixed, paraffin-embedded; DCIS, ductal carcinoma in situ; GST, glutathione S-transferase; DAB, 3–3'diaminobenzidine. Back

4 L-H. Xu, X. Yang, C.A. Bradham, D.A. Brenner, R.J. Craven, and W.G. Cance. The focal adhesion kinase suppresses transformation-associated, anchorage-independent apoptosis in human breast cancer cells, submitted for publication. Back

Received 10/11/99; revised 3/29/00; accepted 4/ 4/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Schaller M. D., Borgman C. A., Cobb B. S., Vines R. R., Reynolds A. B., Parsons J. T. p125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Natl. Acad. Sci. USA, 89: 5192-5196, 1992.[Abstract/Free Full Text]
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Gonadotropin Releasing Hormone Analogue Therapy Alters Signal Transduction Pathways Involving Mitogen-Activated Protein and Focal Adhesion Kinases in Leiomyoma
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