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The Expression of Fascin, an Actin-Bundling Motility Protein, Correlates with Hormone Receptor–Negative Breast Cancer and a More Aggressive Clinical Course

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The Expression of Fascin, an Actin-Bundling Motility Protein, Correlates with Hormone Receptor–Negative Breast Cancer and a More Aggressive Clinical Course 186 Vol. 11, 186–192, January 1, 2005 Clinical Cancer Research The Expression of Fascin, an Actin-Bundling Motility Protein, Correlates with Hormone Receptor–Negative Breast Cancer and a More Aggressive Clinical Course Brian J. Yoder,1 Elisa Tso,2 Marek Skacel,1 site, but rather from local invasion and/or distant metastasis Jim Pettay,1 Shannon Tarr,1 Thomas Budd,2 (2, 3). Metastasis is a complex process involving neovascula- Raymond R. Tubbs,1 Josephine C. Adams,3 and rization, stromal invasion by cancer cells, and infiltration into 1 vascular and lymphatic spaces, survival in the circulation, David G. Hicks extravasation, and growth at a secondary site (2–7). The cellular 1 The Cleveland Clinic Foundation, Department of Anatomic Pathology, mechanisms, which mediate these processes, are poorly 2Taussig Cancer Center, and 3Department of Cell Biology, Lerner Research Institute, Cleveland, Ohio understood, but one requirement is enhancement of cell motility. Augmented movement of cancer cells has been reported to correlate with greater metastatic potential in animal models and a ABSTRACT poor prognosis in human cancer (2). Multiple cellular and extra- The invasion and metastasis of tumor cells is a major cellular factors regulate cell motility, through actions on the cause of mortality in cancer patients. In the current study, we assembly of the actin cytoskeleton. Fascin, is a cytoplasmic investigated the expression of fascin, an actin-bundling protein that functions to bundle cytoplasmic actin filaments, a motility-associated protein, in 210 invasive breast carcino- process which is critical in determining the distribution and ac- mas with corresponding 5-year clinical follow-up. Fascin tivity of the actin cytoskeleton (8). Recently, fascin has emerged expression was compared with hormone receptor (ER/PR) as a key bundling protein in diverse forms of actin-based status, HER2 status, cancer grade, cancer stage, metastasis motility-structures (8). Fascin, is normally expressed in neuronal pattern, disease-free survival, and overall survival. Fascin and mesenchymal cells and is low or absent in epithelia (8, 9). expression was seen in 16% (33/210) of the cases and However, striking up-regulation of fascin has been reported in correlated with ER negativity (22/33, P < 0.001), PR several human epithelial tumors including breast, colon, lung, negativity (21/33, P < 0.001), Bloom-Richardson grade 3 and ovarian carcinomas (10–15). Initial findings implicate fascin (19/29, P < 0.001), and advanced stage (stage 3 or 4, as a potentially significant mediator of tumor cell invasion, and P = 0.04). There was no correlation between fascin ex- an aggressive clinical course. pression and HER2 status or pattern of metastases. Pa- A preliminary study of 58 patients with breast cancer tients whose tumors were positive for fascin showed both a showed that fascin expression correlated significantly with tumor decreased mean disease-free survival (74.44 versus 100.52 grade, DNA ploidy, and correlated inversely with estrogen months, P = 0.002) and mean overall survival (77.58 versus receptor (ER) and progesterone receptor (PR) expression (10). 98.98 months, P = 0.002), independent of tumor stage and These observations suggest that fascin may contribute to the HER2 status, but not independent of ER/PR status or cancer disease progression of some breast cancers. It has been well grade. Given fascin’s role in altering cell motility, over- established in the literature that hormone receptor (ER/PR)– expression may contribute to a more aggressive clinical negative breast cancers have a more aggressive clinical course course in ER/PR-negative breast cancers. If so, then fascin with decreased disease-free and overall survival, compared with may represent a new molecular target for therapeutic hormone receptor–positive tumors (16–18). Furthermore, intervention in patients with ER-negative breast cancer. in vitro experiments have shown that hormone receptor– negative breast cancer cells have increased cell motility and INTRODUCTION increased invasiveness (19, 20). These published observations Breast cancer is one of the leading causes of cancer suggest a possible relationship between hormone receptor neg- mortality for women in the United States today. The American ativity, enhanced cell motility, and fascin expression in invasive Cancer Society estimates that over 200,000 new cases and human breast carcinomas. 40,000 cancer deaths will occur annually (1). In general, most Studies of breast cancer cells in culture have suggested that individuals with cancer die not from the tumor in the primary fascin expression may be regulated, in part, through the overexpression of the membrane receptor tyrosine kinase HER2. MDA-MB435 tumor cells stably transected with HER2 Received 7/8/04; revised 8/11/04; accepted 8/16/04. show a marked increase in mRNA and protein levels of fascin. In Grant support: Internal Research Program Council grant RPC #07384. correlation, cell motility was increased (21). Other studies have The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked shown that the motility responses of fascin-positive breast cancer advertisement in accordance with 18 U.S.C. Section 1734 solely to cells to insulin-like growth factor I depend on fascin protrusions indicate this fact. (22). The current study sought to further investigate the Requests for reprints: D.G. Hicks, Department of Anatomic Pathology, relationship between fascin expression and ER, PR, and HER2 The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-444-5466; Fax: 216-445-6967; E-mail: [email protected]. status as well as explore possible relationships between fascin D2005 American Association for Cancer Research. expression and patient prognosis and patterns of metastasis. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2005 American Association for Cancer Research. Clinical Cancer Research 187 MATERIALS AND METHODS if at least one of the two tissue cores contained at least 5% of Tissue Microarrays. A series of tissue microarrays invasive tumor cells with 2+ or 3+ membranous staining. 2 (TMA) were constructed containing over 210 consecutive pri- Statistics. Bivariate analysis was done via v analysis mary invasive breast carcinomas diagnosed at The Cleveland (fascin positivity versus ER positivity, PR positivity, HER2 Clinic Foundation between 1995 and 1996. The constructed status, tumor stage, and tumor grade) or via one-way ANOVA TMA series consisted of various 8 Â 12 arrays of 1.5 mm tissue with post hoc analysis (percentage of ER-positive or PR-positive cores from archived formalin-fixed, paraffin-embedded surgical cells versus intensity of fascin staining). Survivability data was blocks. Two separate tissue cores of invasive carcinoma, totaling calculated via the generation of Kaplan-Meier curves. Deaths a surface area of 3.5 mm2 , represented each surgical case in the due to causes other than breast cancer were treated as censored TMA series. Each separate tissue core was assigned a unique observations. Subsequent multivariate analysis (death due to TMA location number, which was subsequently linked to an breast cancer versus fascin positivity and either ER, PR, HER2, Institutional Review Board–approved database containing tumor stage, or tumor grade) was done via Cox’s proportional corresponding to a 5-year clinical follow-up. hazards model. All statistics were carried out using Statistical Immunohistochemistry. Fascin, ER, PR, and HER2 Package for the Social Sciences software. Statistical significance expression was assessed via immunohistochemistry. Immuno- was assumed if P < 0.05. Mean follow-up of the study histochemistry was carried out using the fully automated population was 67 months (1-106 months). Ventana Benchmark system. Briefly, a 4-Am-thick unstained section of each TMA were placed onto electrostatically charged RESULTS glass slides and baked to allow for tissue adherence. The glass Characteristics of the Study Population and TMA slides were pretreated with the recommended pretreatment Validation. A summary of the study population is listed in solution provided by Ventana for tissue deparaffinization and Table 1. There were 210 consecutive, newly diagnosed patients antigen retrieval. After primary antibody incubation, antigen with adequate formalin-fixed, paraffin-embedded tissue at our detection was done via peroxidase/3,3V-diaminobenzidine after a institution from 1995 through 1996. The majority of these (168) secondary biotinylated antibody/streptavidin amplification step. For double-labeled sections, alkaline phosphatase red was used for secondary antigen detection. Lastly, a hematoxylin counter- Table 1 Clinical and pathologic characteristics for the study population (210 patients) stain was applied. Immunohistochemistry scoring was done by two independent observers (B.Y., D.H.) completely blinded to Criteria Number % the clinical outcome data. Age (y) The expression of fascin (DAKO, clone 55K-2) was first < 50 66/210 31 tested on positive control tissue (cytoplasmic staining of Reed- > 50 144/210 69 Tumor size Sternberg cells in Hodgkin’s disease) using serial dilutions to T1 128/210 61 determine the optimal antibody concentration (1:50). Each T2 56/210 27 separate tissue core was scored on a 0 to 3+ intensity scale T3 11/210 5 (1+ = weak cytoplasmic and membrane staining, 2+ = T4 11/210 5 Unknown 4/210 2 moderately intense staining,
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