期刊论文详细信息
Diagnostic Pathology
Beta 1 integrin predicts survival in breast cancer: a clinicopathological and immunohistochemical study
Eduardo IC Beltrão1  Alfredo Ribeiro-Silva3  Juliana S Zanetti3  Petra Barros dos Santos2 
[1] Department of Biochemistry, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil;Department of Pathology, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Avenida Professor Moraes Rêgo S/N, 50670-901, Recife, Pernambuco, Brazil;Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil
关键词: Prognosis;    Immunohistochemistry;    Tissue microarray;    β1 integrin;   
Others  :  807996
DOI  :  10.1186/1746-1596-7-104
 received in 2012-05-28, accepted in 2012-08-10,  发布年份 2012
PDF
【 摘 要 】

Background

The main focus of several studies concerned with cancer progression and metastasis is to analyze the mechanisms that allow cancer cells to interact and quickly adapt with their environment. Integrins, a family of transmembrane glycoproteins, play a major role in invasive and metastatic processes. Integrins are involved in cell adhesion in both cell-extracellular matrix and cell-cell interactions, and particularly, β1 integrin is involved in proliferation and differentiation of cells in the development of epithelial tissues. This work aimed to investigate the putative role of β1 integrin expression on survival and metastasis in patients with breast invasive ductal carcinoma (IDC). In addition, we compared the expression of β1 integrin in patients with ductal carcinoma in situ (DCIS).

Methods

Through tissue microarray (TMA) slides containing 225 samples of IDC and 67 samples of DCIS, β1 integrin expression was related with several immunohistochemical markers and clinicopathologic features of prognostic significance.

Results

β1 integrin was overexpressed in 32.8% of IDC. In IDC, β1 integrin was related with HER-2 (p = 0.019) and VEGF (p = 0.011) expression and it had a significant relationship with metastasis and death (p = 0.001 and p = 0.05, respectively). Kaplan-Meier survival analysis showed that the overexpression of this protein is very significant (p = 0.002) in specific survival (number of months between diagnosis and death caused by the disease). There were no correlation between IDC and DCIS (p = 0.559) regarding β1 integrin expression.

Conclusions

Considering that the expression of β1 integrin in breast cancer remains controversial, specially its relation with survival of patients, our findings provide further evidence that β1 integrin can be a marker of poor prognosis in breast cancer.

Virtual slides

The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/6652215267393871 webcite

【 授权许可】

   
2012 dos Santos et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140708130827278.pdf 1158KB PDF download
Figure 4. 201KB Image download
Figure 3. 45KB Image download
Figure 2. 45KB Image download
Figure 1. 45KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】
  • [1]Hynes RO: Integrins: bidirectional, allosteric signaling machines. Cell 2002, 110(6):673-687.
  • [2]Melker AA, Sonnenberg A: Integrins: alternative splicing as a mechanism to regulate ligand binding and integrin signaling events. Bioessays 1999, 21(6):499-509.
  • [3]Gilcrease MZ: Integrin signaling in epithelial cells. Cancer Lett 2007, 247(1):1-25.
  • [4]Seftor REB: Role of the beta3 integrin subunit in human primary melanoma progression: multifunctional activities associated with alpha(v)beta3 integrin expression. Am J Pathol 1998, 153(5):1347-1351.
  • [5]Ellis SJ, Tanentzapf G: Integrin-mediated adhesion and stem-cell-niche interactions. Cell Tissue Res 2010, 339(1):121-130.
  • [6]Tavassoli FA, Devilee P: World health organization classification of tumours: pathology and genetics of tumours of the breast and female genital organs. IARCPress, Lyon; 2003.
  • [7]Bombonati A, Sgroi DC: The molecular pathology of breast cancer progression. J Pathol 2011, 223(2):307-317.
  • [8]Mizejewski GJ: Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med 1999, 222(2):124-138.
  • [9]Weigelt B, Peterse JL, Van't Veer LJ: Breast cancer metastasis: markers and models. Nat Rev Cancer 2005, 5(8):591-602.
  • [10]Li N, Zhang Y, Naylor MJ, Schatzmann F, Maurer F, Wintermantel T, Schuetz G, Mueller U, Streuli CH, Hynes NE: Beta integrins regulates mammary proliferation and maintain the integrity of mammary alveoli. EMBO J 2005, 24(11):1942-1953.
  • [11]Desgrosellier JS, Cheresh DA: Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010, 10(1):9-22.
  • [12]Park CC, Zhang HJ, Yao ES, Park CJ, Bissell MJ: Beta1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res 2008, 68(11):4398-4405.
  • [13]Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, Powers D, Chao DT, Dubridge RB, Ramakrishnan V: A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 2007, 5(61):1-11.
  • [14]Ricart AD, Tolcher AW, Liu G, Holen K, Schwartz G, Albertini M, Weiss G, Yazji S, Ng C, Wilding G: Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: a phase I, pharmacokinetic, and biological correlative study. Clin Cancer Res 2008, 14(23):7924-7929.
  • [15]Van Diest PJ: Ductal carcinoma in situ in breast carcinogenesis. J Pathol 1999, 187(4):383-384.
  • [16]Ramirez NE, Zhang Z, Madamanchi A, Boyd KL, O'Rear LD, Nashabi A, Li Z, Dupont WD, Zijlstra A, Zutter MM: The α2β1 integrin is a metastasis suppressor in mouse models and human cancer. J Clin Invest 2011, 121(1):226-237.
  • [17]Koistinen P, Ahonen M, Kähäri VM, Heino J: alphaV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma. Int J Cancer 2004, 112(1):61-70.
  • [18]Zanetti JS, Soave DF, Oliveira-Costa JP, da Silveira GG, Ramalho LN, Garcia SB, Zucoloto S, Ribeiro-Silva A: The role of tumor hypoxia in MUC1-positive breast carcinomas. Virchows Arch 2011, 459(4):367-375.
  • [19]Ribeiro-Silva A, Moutinho MA H, Moura B, Vale FR, Zucoloto S: Expression of checkpoint kinase 2 in breast carcinomas: correlation with key regulators of tumor cell proliferation, angiogenesis, and survival. Histol Histopathol 2006, 21(4):373-382.
  • [20]Yao ES, Zhang H, Chen YY, Lee B, Chew K, Moore D, Park C: Increased beta1 integrin is associated with decreased survival in invasive breast cancer. Cancer Res 2007, 67(2):659-664.
  • [21]Petricevic B, Vrbanec D, Jakic-Razumovic J, Brcic I, Rabic D, Badovinac T, Ozimec E, Bali V: Expression of Toll-like receptor 4 and beta 1 integrin in breast cancer. Med Oncol 2012, 29:486-494.
  • [22]Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology/College of American Pathologists: American society of clinical oncology/college of american pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007, 131:18-43.
  • [23]Oliveira-Costa JP, Zanetti J, Oliveira LR, Soares FA, Ramalho LZ, Silva Ramalho F, Garcia SB, Ribeiro-Silva A: Significance of topoisomerase IIIβ expression in breast ductal carcinomas: strong associations with disease-specific survival and metastasis. Hum Pathol 2010, 41(11):1624-1630.
  • [24]Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, Harris AL: Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 2001, 61(21):7992-7998.
  • [25]Hammond ME, Hayes DF, Dowsett M, et al.: American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010, 28(16):2784-2795.
  • [26]Fountzilas G, Dafni U, Bobos M, Batistatou A, Kotoula V, Trihia H, Malamou-Mitsi V, Miliaras S, Chrisafi S, Papadopoulos S, Sotiropoulou M, Filippidis T, Gogas H, Koletsa T, Bafaloukos D, Televantou D, Kalogeras KT, Pectasides D, Skarlos DV, Koutras A, Dimopoulos MA: Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel. PLoS One 2012, 7(6):e37946.
  • [27]Ercan C, van Diest PJ, van der Ende B, Hinrichs J, Bult P, Buerger H, van der Wall E, Derksen PW: p53 mutations in classic and pleomorphic invasive lobular carcinoma of the breast. Cell Oncol 2012, 35:111-118.
  • [28]O'connell JT, Zhi-Ming S, Ehud D, Basbaum CB, Barsky SH: Altered mucin expression is a field change that accompanies mucinous (colloid) breast carcinoma histogenesis. Hum Pathol 1998, 29(12):1517-1523.
  • [29]Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998, 4(7):844-847.
  • [30]Zhang DH, Salto-Tellez M, Putti TC, Do E, Koay ES-C: Reliability of tissue microarrays in detecting protein expression and gene amplification in breast cancer. Mod Pathol 2003, 16(1):79-85.
  • [31]Hassan S, Ferrario C, Mamo A, Basik M: Tissue microarrays: emerging standard for biomarker validation. Curr Opin Biotechnol 2008, 19(1):19-25.
  • [32]Lawson MH, Cummings NM, Rassl DM, Vowler SL, Wickens M, Howat WJ, Brenton JD, Murphy G, Rintoul RC: Bcl-2 and β1-integrin predict survival in a tissue microarray of small cell lung cancer. Br J Cancer 2010, 103(11):1710-1715.
  • [33]Varner JA, Cheresh DA: Integrins and cancer. Curr Opin Cell Biol 1996, 8(5):724-730.
  • [34]Guo W, Pylayeva Y, Pepe A, Yoshioka T, Muller WJ, Inghirami G, Giancotti FG: Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 2006, 126(3):489-502.
  • [35]Brakebusch C, Hirsch E, Potocnik A, Fässler R: Genetic analysis of β1 integrin function: confirmed, new and revised roles for a crucial family of cell adhesion molecules. J Cell Sci 1997, 110(23):2895-2904.
  • [36]Guo L, Zhang F, Cai Y, Liu T: Expression profiling of integrins in lung cancer cells. Pathol Res Pract 2009, 205(12):847-853.
  • [37]Dingemans AM, van den Boogaart V, Vosse BA, van Suylen RJ, Griffioen AW, Thijssen VL: Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer. Mol Cancer 2010, 9(152):1-9.
  • [38]Kren A, Baeriswyl V, Lehembre F, Wunderlin C, Strittmatter K, Antoniadis H, Fässler R, Cavallaro U, Christofori G: Increased tumor cell dissemination and cellular senescence in the absence of beta1-integrin function. EMBO J 2007, 26(12):2832-2842.
  • [39]Gonzalez MA, Pinder SE, Wencyk PM, Bell JA, Elston CW, Nicholson RI, Robertson JF, Blamey RW, Ellis IO: An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma-catenins, and alpha2- and beta1- integrins in invasive breast cancer. J Pathol 1999, 187(5):523-529.
  • [40]Lanzafame S, Emmanuele C, Torrisi A: Correlation of alpha 2 beta 1 integrin expression with histological type and hormonal receptor status in breast carcinomas. Pathol Res Pract 1996, 192(10):1031-1038.
  • [41]Berry MG, Gui GP, Wells CA, Carpenter R: Integrin expression and survival in human breast cancer. Eur J Surg Oncol 2004, 30(5):484-489.
  • [42]Adachi M, Taki T, Higashiyama M, Kohno N, Inufusa H, Miyake M: Significance of integrin alpha5 gene expression as a prognostic factor in node-negative non-small cell lung cancer. Clin Cancer Res 2000, 6(1):96-101.
  • [43]Ahmed N, Riley C, Rice G, Quinn M: Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment. Clin Exp Metastasis 2005, 22(5):391-402.
  • [44]Bottger TC, Maschek H, Lobo M, Gottwohl RG, Brenner W, Junginger T: Prognostic value of immunohistochemical expression of beta-1 integrin in pancreatic carcinoma. Oncology 1999, 56(4):308-313.
  • [45]Park CC, Zhang H, Pallavicini M, Gray JW, Baehner F, Park CJ, Bissell MJ: Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth and distinguishes malignant form normal phenotype in three dimensional cultures and in vivo. Cancer Res 2006, 66(3):1526-1535.
  • [46]Adams JC, Watt FM: Regulation of development and differentiation by the extracellular matrix. Development 1993, 117(4):1183-1198.
  • [47]Hayashida T, Jones JC, Lee CK, Schnaper HW: Loss of beta1-integrin enhances TGF-beta1-induced collagen expression in epithelial cells via increased alphavbeta3-integrin and Rac1 activity. J Biol Chem 2010, 285(40):30741-39751.
  • [48]Walker JL, Fournier AK, Assoian RK: Regulation of growth factor signaling and cell cycle progression by cell adhesion and adhesion-dependent changes in cellular tension. Cytokine Growth Factor Rev 2005, 16(4-5):395-405.
  • [49]Klein EA, Yung Y, Castagnino P, Kothapalli D, Assoian RK: Cell adhesion, cellular tension, and cell cycle control. Methods Enzymol 2007, 426:155-175.
  • [50]Morello V, Cabodi S, Sigismund S, Camacho-Leal MP, Repetto D, Volante M, Papotti M, Turco E, Defilippi P: β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells. Oncogene 2011, 30(39):4087-4096.
  • [51]Lee TH, Seng S, Li H, Kennel SJ, Avraham HK, Avraham S: Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of alpha6beta1 integrin in angiogenesis. J Biol Chem 2006, 281(52):40450-40460.
  • [52]Bloch W, Forsberg E, Lentini S, Brakebusch C, Martin K, Krell HW, Weidle UH, Addicks K, Fässler R: Beta 1 integrin is essential for teratoma growth and angiogenesis. J Cell Biol 1997, 139(1):265-278.
  • [53]White DE, Kurpios NA, Zuo D, Hassell JA, Blaess S, Mueller U, Muller WJ: Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 2004, 6(2):159-170.
  • [54]Shimizu H, Seiki T, Asada M, Yoshimatsu K, Koyama N: Alpha6beta1 integrin induces proteasome-mediated cleavage of erbB2 in breast cancer cells. Oncogene 2003, 22(6):831-839.
  • [55]Spangenberg C, Lausch EU, Trost TM, Prawitt D, May A, Keppler R, Fees SA, Reutzel D, Bell C, Schmitt S, Schiffer IB, Weber A, Brenner W, Hermes M, Sahin U, Türeci O, Koelbl H, Hengstler JG, Zabel BU: ERBB2-mediated transcriptional up-regulation of the alpha5beta1 integrin fibronectin receptor promotes tumor cell survival under adverse conditions. Cancer Res 2006, 66(7):3715-3725.
  • [56]Borg A, Tandon AK, Sigurdsson H, Clark GM, Fernö M, Fuqua SA, Killander D, McGuire WL: HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res 1990, 50(14):4332-4337.
  • [57]Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86(3):353-364.
  文献评价指标  
  下载次数:39次 浏览次数:24次