Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer

BMC Cancer

Seunghwan Lim⁶  Byoung Kwon Yoo²  Hae-Suk Kim⁶  Hannah L Gilmore¹  Yonghun Lee⁵  Hyun-pil Lee¹  Seong-Jin Kim⁴  John Letterio³  Hyoung-gon Lee¹ 

[1] Department Pathology, Case Western Reserve University School of Medicine, 2103 Cornell Road, Cleveland, OH 44106, USA

[2] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

[3] The Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals Rainbow Children's Hospital, Cleveland, OH 44106, USA

[4] CHA Cancer Institute, CHA University, Seoul, 135-081, Korea

[5] Department Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

[6] Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 2103 Cornell Road, Cleveland, OH 44106, USA

关键词: p27^kip1;    Invasion;    Breast cancer;    Apoptosis;    Amyloid-β precursor protein;    AKT;   

Others  :  1117920
DOI  :  10.1186/1471-2407-14-928

 received in 2014-04-15, accepted in 2014-12-05,  发布年份 2014

【 摘 要 】

Background

Amyloid-β precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. Recently, the increased expression of APP in multiple types of cancers has been reported where it has significant correlation with the cancer cell proliferation. However, the function of APP in the pathogenesis of breast cancer has not previously been determined. In this study, we studied the pathological role of APP in breast cancer and revealed its potential mechanism.

Methods

The expression level of APP in multiple breast cancer cell lines was measured by Western blot analysis and the breast cancer tissue microarray was utilized to analyze the expression pattern of APP in human patient specimens. To interrogate the functional role of APP in cell growth and apoptosis, the effect of APP knockdown in MDA-MB-231 cells were analyzed. Specifically, multiple signal transduction pathways and functional alterations linked to cell survival and motility were examined in in vivo animal model as well as in vitro cell culture with the manipulation of APP expression.

Results

We found that the expression of APP is increased in mouse and human breast cancer cell lines, especially in the cell line possessing higher metastatic potential. Moreover, the analysis of human breast cancer tissues revealed a significant correlation between the level of APP and tumor development. Knockdown of APP (APP-kd) in breast cancer cells caused the retardation of cell growth in vitro and in vivo, with both the induction of p27^kip1 and caspase-3-mediated apoptosis. APP-kd cells also had higher sensitivity to treatment of chemotherapeutic agents, TRAIL and 5-FU. Such anti-tumorigenic effects shown in the APP-kd cells partially came from reduced pro-survival AKT activation in response to IGF-1, leading to activation of key signaling regulators for cell growth, survival, and pro-apoptotic events such as GSK3-β and FOXO1. Notably, knock-down of APP in metastatic breast cancer cells limited cell migration and invasion ability upon stimulation of IGF-1.

Conclusion

The present data strongly suggest that the increase of APP expression is causally linked to tumorigenicity as well as invasion of aggressive breast cancer and, therefore, the targeting of APP may be an effective therapy for breast cancer.

【 授权许可】

   
2014 Lim et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]O’Brien RJ, Wong PC: Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 2011, 34:185-204.
• [2]Hardy JA, Higgins GA: Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992, 256(5054):184-185.
• [3]De Strooper B, Annaert W: Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 2000, 113(Pt 11):1857-1870.
• [4]Jacobsen KT, Iverfeldt K: Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors. Cell Mol Life Sci 2009, 66(14):2299-2318.
• [5]Sheng B, Song B, Zheng Z, Zhou F, Lu G, Zhao N, Zhang X, Gong Y: Abnormal cleavage of APP impairs its functions in cell adhesion and migration. Neurosci Lett 2009, 450(3):327-331.
• [6]Sosa LJ, Bergman J, Estrada-Bernal A, Glorioso TJ, Kittelson JM, Pfenninger KH: Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidance. PLoS One 2013, 8(5):e64521.
• [7]Baratchi S, Evans J, Tate WP, Abraham WC, Connor B: Secreted amyloid precursor proteins promote proliferation and glial differentiation of adult hippocampal neural progenitor cells. Hippocampus 2012, 22(7):1517-1527.
• [8]Hoffmann J, Twiesselmann C, Kummer MP, Romagnoli P, Herzog V: A possible role for the Alzheimer amyloid precursor protein in the regulation of epidermal basal cell proliferation. Eur J Cell Biol 2000, 79(12):905-914.
• [9]Pietrzik CU, Hoffmann J, Stober K, Chen CY, Bauer C, Otero DA, Roch JM, Herzog V: From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. Proc Natl Acad Sci U S A 1998, 95(4):1770-1775.
• [10]Meng JY, Kataoka H, Itoh H, Koono M: Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer 2001, 92(1):31-39.
• [11]Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A: Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res 2003, 63(21):7032-7037.
• [12]Krause K, Karger S, Sheu SY, Aigner T, Kursawe R, Gimm O, Schmid KW, Dralle H, Fuhrer D: Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis. J Endocrinol 2008, 198(2):291-299.
• [13]Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J, Urano T, Sakaki Y, Shirahige K, Sasano H, Takahashi S, Kitamura T, Ouchi Y, Aburatani H, Inoue S: Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res 2009, 69(1):137-142.
• [14]Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, Wirths O, Bayer TA: Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem 2010, 285(14):10678-10689.
• [15]Takagi K, Ito S, Miyazaki T, Miki Y, Shibahara Y, Ishida T, Watanabe M, Inoue S, Sasano H, Suzuki T: Amyloid precursor protein (APP) in human breast cancer: an androgen-induced gene associated with cell proliferation. Cancer Sci 2013, 104(11):1532-1538.
• [16]Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ: A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci 2007, 27(52):14459-14469.
• [17]Young-Pearse TL, Chen AC, Chang R, Marquez C, Selkoe DJ: Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev 2008, 3:15. BioMed Central Full Text
• [18]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. Cancer J Clin 2011, 61(2):69-90.
• [19]Hong S, Lim S, Li AG, Lee C, Lee YS, Lee EK, Park SH, Wang XJ, Kim SJ: Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat Immunol 2007, 8(5):504-513.
• [20]Harris JA, Devidze N, Verret L, Ho K, Halabisky B, Thwin MT, Kim D, Hamto P, Lo I, Yu GQ, Palop JJ, Masliah E, Mucke L: Transsynaptic progression of amyloid-beta-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 2010, 68(3):428-441.
• [21]Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J: Genes that mediate breast cancer metastasis to lung. Nature 2005, 436(7050):518-524.
• [22]Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, Wakefield LM: TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 2003, 112(7):1116-1124.
• [23]Miller FR, Soule HD, Tait L, Pauley RJ, Wolman SR, Dawson PJ, Heppner GH: Xenograft model of progressive human proliferative breast disease. J Natl Cancer Inst 1993, 85(21):1725-1732.
• [24]Aslakson CJ, Miller FR: Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 1992, 52(6):1399-1405.
• [25]Mattson MP: Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 1997, 77(4):1081-1132.
• [26]Kummer C, Wehner S, Quast T, Werner S, Herzog V: Expression and potential function of beta-amyloid precursor proteins during cutaneous wound repair. Exp Cell Res 2002, 280(2):222-232.
• [27]Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999, 13(12):1501-1512.
• [28]Caldon CE, Daly RJ, Sutherland RL, Musgrove EA: Cell cycle control in breast cancer cells. J Cell Biochem 2006, 97(2):261-274.
• [29]Chu IM, Hengst L, Slingerland JM: The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev 2008, 8(4):253-267.
• [30]Wander SA, Zhao D, Slingerland JM: p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies. Clin Cancer Res 2011, 17(1):12-18.
• [31]Mahalingam D, Szegezdi E, Keane M, de Jong S, Samali A: TRAIL receptor signalling and modulation: Are we on the right TRAIL? Cancer Treat Rev 2009, 35(3):280-288.
• [32]Joensuu H, Gligorov J: Adjuvant treatments for triple-negative breast cancers. Ann Oncol 2012, 23(Suppl 6):vi40-vi45.
• [33]Lee GY, Kenny PA, Lee EH, Bissell MJ: Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods 2007, 4(4):359-365.
• [34]Schmeichel KL, Bissell MJ: Modeling tissue-specific signaling and organ function in three dimensions. J Cell Sci 2003, 116(Pt 12):2377-2388.
• [35]Weigelt B, Bissell MJ: Unraveling the microenvironmental influences on the normal mammary gland and breast cancer. Semin Cancer Biol 2008, 18(5):311-321.
• [36]Kenny PA, Lee GY, Myers CA, Neve RM, Semeiks JR, Spellman PT, Lorenz K, Lee EH, Barcellos-Hoff MH, Petersen OW, Gray JW, Bissell MJ: The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 2007, 1(1):84-96.
• [37]Hollestelle A, Elstrodt F, Nagel JH, Kallemeijn WW, Schutte M: Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res 2007, 5(2):195-201.
• [38]Chakrabarty A, Bhola NE, Sutton C, Ghosh R, Kuba MG, Dave B, Chang JC, Arteaga CL: Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. Cancer Res 2013, 73(3):1190-1200.
• [39]Rexer BN, Arteaga CL: Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. Cancer Res 2013, 73(13):3817-3820.
• [40]Tzivion G, Dobson M, Ramakrishnan G: FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 2011, 1813(11):1938-1945.
• [41]Clarke RB: p27KIP1 phosphorylation by PKB/Akt leads to poor breast cancer prognosis. Breast Cancer Res 2003, 5(3):162-163. BioMed Central Full Text
• [42]Zheng H, Jiang M, Trumbauer ME, Hopkins R, Sirinathsinghji DJ, Stevens KA, Conner MW, Slunt HH, Sisodia SS, Chen HY, Van der Ploeg LH: Mice deficient for the amyloid precursor protein gene. Ann N Y Acad Sci 1996, 777:421-426.
• [43]Goodarzi H, Zhang S, Buss CG, Fish L, Tavazoie S, Tavazoie SF: Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins. Nature 2014, 513(7517):256-260.
• [44]King TD, Suto MJ, Li Y: The Wnt/beta-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J Cell Biochem 2012, 113(1):13-18.
• [45]Incassati A, Chandramouli A, Eelkema R, Cowin P: Key signaling nodes in mammary gland development and cancer: beta-catenin. Breast Cancer Res 2010, 12(6):213. BioMed Central Full Text
• [46]Yang JY, Hung MC: Deciphering the role of forkhead transcription factors in cancer therapy. Curr Drug Targets 2011, 12(9):1284-1290.
• [47]Srinivasula SM, Ashwell JD: IAPs: what’s in a name? Mol Cell 2008, 30(2):123-135.
• [48]Jimenez S, Torres M, Vizuete M, Sanchez-Varo R, Sanchez-Mejias E, Trujillo-Estrada L, Carmona-Cuenca I, Caballero C, Ruano D, Gutierrez A, Vitorica J: Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK-3beta pathway in Alzheimer mouse model. J Biol Chem 2011, 286(21):18414-18425.
• [49]Larue L, Bellacosa A: Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 2005, 24(50):7443-7454.
• [50]Gilles C, Polette M, Mestdagt M, Nawrocki-Raby B, Ruggeri P, Birembaut P, Foidart JM: Transactivation of vimentin by beta-catenin in human breast cancer cells. Cancer Res 2003, 63(10):2658-2664.
• [51]Roxanis I: Occurrence and significance of epithelial-mesenchymal transition in breast cancer. J Clin Pathol 2013, 66(6):517-521.