Focal adhesion kinase (FAK) is a protein tyrosine kinase expressed in invasive breast cancer that regulates antiapoptotic signaling. We have examined FAK expression by immunohistochemistry using anti-FAK 4.47 in breast tumor samples from a large population-based, case-control study of women participating in the University of North Carolina Breast Specialized Programs of Research Excellence (SPORE), Carolina Breast Cancer Study. In this population, 629 formalin-fixed, paraffin-embedded tissue sections were stained for FAK and scored as high (3 þ or 4 þ intensity and Z90% positive cells) or otherwise. High FAK expression was associated with poor prognostic indicators including high mitotic index (410 mitoses per 10 consecutive highpower fields), nuclear grade 3, architectural grade 3, estrogen and progesterone receptor negative, and HER-2/ neu overexpressed using CB11 antibody. The association of high FAK expression with HER-2/neu overexpression lends further support that HER-2/neu and FAK collaborate to promote tumorigenesis. The presence of strong FAK expression in many high grade, estrogen-and progesterone-negative breast carcinomas indicates that FAK may be an attractive target for therapeutic intervention.
Focal adhesion kinase (FAK) is a protein tyrosine kinase that is overexpressed in a subset of invasive breast cancers. FAK transmits signals that mediate several functions including tumor cell proliferation, migration, adhesion and survival. We used immunohistochemical techniques to assess FAK expression in patients with fibrocystic disease (FCD), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC). Formalin-fixed, paraffin-embedded (FFPE) tissue sections were obtained from 119 patients (12 FCD, 38 ADH, 51 DCIS and 18 IDC). The anti-FAK 4.47 monoclonal antibody was used to detect FAK expression. FAK expression was scored as high (3 or 4 intensity and > or =90% positive cells) or low. The DCIS tissue sections demonstrated high FAK expression in 34/51 (66%) of the sections. High FAK expression was demonstrated in 6/18 (33%) of the IDC tissue sections and 8/38 (21%) of the ADH tissue sections. None (0/12) of the FCD tissues sections stained high for FAK. The pattern of FAK expression in DCIS was significantly higher than ADH (p < 0.0001) and IDC (p = 0.02). We conclude that FAK overexpression in preinvasive, DCIS tumors precedes tumor cell invasion or metastasis, suggesting that FAK may function as a survival signal and be an early event in breast tumorigenesis.
PITX2 methylation status assessed by EpiChip PITX2 identifies patients with prostate cancer who are most likely to have biochemical recurrence. This test independently adds to the prognostic information provided by standard clinicopathological analysis, improving prostatectomy case stratification into those at high and low risk for biochemical recurrence. This new clinical tool would be of particular benefit to assess intermediate risk cases (Gleason 7) in which risk stratification remains a challenge.
Focal adhesion kinase (FAK) is overexpressed in a number of tumors, including breast cancer. Another marker of breast cancer tumorigenesis is the tumor suppressor gene p53 that is frequently mutated in breast cancer. In the present study, our aim was to find a correlation between FAK overexpression, p53 expression and mutation status in a population-based series of invasive breast cancer tumors from the Carolina Breast Cancer Study. Immunohistochemical analyses of 622 breast cancer tumors revealed that expression of FAK and p53 were highly correlated (p 5 0.0002) and FAK positive tumors were 1.8 times more likely to be p53 positive compared to FAK negative tumors [odds ratio (OR) 5 1.8; 95% Confidence Interval (CI) 1.2-2.8, adjusted for age, race and stage at diagnosis]. Tumors positive for p53 expression showed higher intensity of FAK staining (p < 0.0001) and higher percent of FAK positive staining (p < 0.0005). From the same study, we evaluated 596 breast tumors for mutations in the p53 gene, using single strand conformational polymorphism and sequencing. Statistical analyses were performed to determine the correlation between p53 mutation status and FAK expression in these tumors. We found that FAK expression and p53 mutation were positively correlated (p < 0.0001) and FAK positive tumors were 2.5 times more likely to be p53 mutation positive compared to FAK negative tumors [adjusted OR 5 2.5, 95% CI 1.6-3.9]. This is the first analysis demonstrating a high correlation between FAK expression and p53 mutations in a population-based series of breast tumors. ' UICCKey words: p53; focal adhesion kinase; breast cancer; tumor Tumor suppressor p53 is one of the major markers of human tumorigenesis and is mutated in almost 50% of all tumors. 1 Following induction by a variety of cell stresses such as DNA damage, hypoxia and oncogene activation, p53 up-regulates a number of genes that can promote cell death and growth arrest such as p21, Bax, cyclin G, GADD45 (reviewed in Ref. 2). Recently, it was shown that p53 can also repress promoter activities of a number of anti-apoptotic genes and cell-cycle genes (survivin, cyclin B1, cdc2, cdc25 c, stathmin, Map4, bcl-2 and FAK). 3 Focal adhesion kinase (FAK) is a nonreceptor cytoplasmic protein tyrosine kinase that controls a number of cellular signaling pathways, including proliferation, cell spreading, motility, angiogenesis, invasion and survival. 4 FAK is overexpressed in many types of tumors including breast cancer tumors. 5 We have shown that FAK upregulation occurred in early stages of breast tumorigenesis. 5,6 In addition, increased FAK mRNA and protein expression has been demonstrated in adenomatous tissues and matched samples of colorectal carcinoma and liver metastases. 7,8 The first report on indirect functional link between FAK and tumor suppressor gene p53 was reported by Ilic et al. 9 The authors demonstrated that p53 controls survival signals from the extracellular matrix transduced by FAK in anchorage-dependent cells. 9 Recently, cloning and characterizat...
A wide array of biomarkers is being investigated as predictors of prostate cancer (PCa) diagnosis and recurrence. We compared the expression of a small panel of these biomarkers as a function of race among men undergoing radical prostatectomy (RP). Prostate needle biopsy specimens from 131 patients treated with RP at the Durham Veterans Affairs Medical Center were hematoxylin and eosin stained and immunofluorescent assayed for α-methylacyl CoA racemase (AMACR), androgen receptor (AR) and Ki67. Proprietary image analysis was used to identify six biometric feature combinations that were significantly associated with progression in a previous study. Analysis of population characteristics, stratified by race, was performed using rank-sum and χ(2)-test. The effect of race on expression of these biomarker profiles was analyzed using multivariate linear regression. All six biomarker features were expressed at higher levels in black men than white men, with Norm AR (P=0.006) and Ki67 (P=0.02) attaining statistical significance. On multivariate analysis, all markers were expressed at higher levels in black men, with Norm AR (P=0.001), Ki67 (P=0.007) and Ki67/lum (P=0.022) reaching significance. These data support the hypothesis that PCa may be biologically more aggressive among black men.
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