Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

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

Authors: Seunghwan Lim, Byoung Kwon Yoo, Hae-Suk Kim, Hannah L Gilmore, Yonghun Lee, Hyun-pil Lee, Seong-Jin Kim, John Letterio, Hyoung-gon Lee

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

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 p27kip1 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.
Appendix
Available only for authorised users
Literature
1.
O’Brien RJ, Wong PC: Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 2011, 34: 185-204. 10.1146/annurev-neuro-061010-113613.CrossRefPubMedPubMedCentral
2.
Hardy JA, Higgins GA: Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992, 256 (5054): 184-185. 10.1126/science.1566067.CrossRefPubMed
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.PubMed
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. 10.1007/s00018-009-0020-8.CrossRefPubMed
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. 10.1016/j.neulet.2008.11.046.CrossRefPubMed
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): e64521-10.1371/journal.pone.0064521.CrossRefPubMedPubMedCentral
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. 10.1002/hipo.20988.CrossRefPubMed
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. 10.1078/0171-9335-00117.CrossRefPubMed
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. 10.1073/pnas.95.4.1770.CrossRefPubMedPubMedCentral
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. 10.1002/1097-0215(200102)9999:9999<::AID-IJC1155>3.0.CO;2-H.CrossRefPubMed
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.PubMed
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. 10.1677/JOE-08-0005.CrossRefPubMed
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. 10.1158/0008-5472.CAN-08-3633.CrossRefPubMed
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. 10.1074/jbc.M109.057836.CrossRefPubMedPubMedCentral
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. 10.1111/cas.12239.CrossRefPubMed
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. 10.1523/JNEUROSCI.4701-07.2007.CrossRefPubMed
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: 15-10.1186/1749-8104-3-15.CrossRefPubMedPubMedCentral
18.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRef
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. 10.1038/ni1451.CrossRefPubMed
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. 10.1016/j.neuron.2010.10.020.CrossRefPubMedPubMedCentral
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. 10.1038/nature03799.CrossRefPubMedPubMedCentral
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. 10.1172/JCI200318899.CrossRefPubMedPubMedCentral
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. 10.1093/jnci/85.21.1725.CrossRefPubMed
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.PubMed
25.
Mattson MP: Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev. 1997, 77 (4): 1081-1132.PubMed
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. 10.1006/excr.2002.5631.CrossRefPubMed
27.
Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999, 13 (12): 1501-1512. 10.1101/gad.13.12.1501.CrossRefPubMed
28.
Caldon CE, Daly RJ, Sutherland RL, Musgrove EA: Cell cycle control in breast cancer cells. J Cell Biochem. 2006, 97 (2): 261-274. 10.1002/jcb.20690.CrossRefPubMed
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. 10.1038/nrc2347.CrossRef
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. 10.1158/1078-0432.CCR-10-0752.CrossRefPubMed
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. 10.1016/j.ctrv.2008.11.006.CrossRefPubMed
32.
Joensuu H, Gligorov J: Adjuvant treatments for triple-negative breast cancers. Ann Oncol. 2012, 23 (Suppl 6): vi40-vi45.CrossRefPubMed
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. 10.1038/nmeth1015.CrossRefPubMedPubMedCentral
34.
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. 10.1016/j.semcancer.2008.03.013.CrossRefPubMedPubMedCentral
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. 10.1016/j.molonc.2007.02.004.CrossRefPubMedPubMedCentral
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. 10.1158/1541-7786.MCR-06-0263.CrossRefPubMed
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. 10.1158/0008-5472.CAN-12-2440.CrossRefPubMed
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. 10.1158/0008-5472.CAN-13-0687.CrossRefPubMedPubMedCentral
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. 10.1016/j.bbamcr.2011.06.002.CrossRefPubMed
41.
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. 10.1111/j.1749-6632.1996.tb34456.x.CrossRefPubMed
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. 10.1038/nature13466.CrossRefPubMedPubMedCentral
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. 10.1002/jcb.23350.CrossRefPubMed
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): 213-10.1186/bcr2723.CrossRefPubMedPubMedCentral
46.
Yang JY, Hung MC: Deciphering the role of forkhead transcription factors in cancer therapy. Curr Drug Targets. 2011, 12 (9): 1284-1290. 10.2174/138945011796150299.CrossRefPubMedPubMedCentral
47.
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. 10.1074/jbc.M110.209718.CrossRefPubMedPubMedCentral
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. 10.1038/sj.onc.1209091.CrossRefPubMed
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.PubMed
51.
Roxanis I: Occurrence and significance of epithelial-mesenchymal transition in breast cancer. J Clin Pathol. 2013, 66 (6): 517-521. 10.1136/jclinpath-2012-201348.CrossRefPubMed
Metadata
Title
Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer
Authors
Seunghwan Lim
Byoung Kwon Yoo
Hae-Suk Kim
Hannah L Gilmore
Yonghun Lee
Hyun-pil Lee
Seong-Jin Kim
John Letterio
Hyoung-gon Lee
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-928

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

Multimodal therapy in treatment of rectal cancer is associated with improved survival and reduced local recurrence - a retrospective analysis over two decades

Research article

Fibulin-5 inhibits hepatocellular carcinoma cell migration and invasion by down-regulating matrix metalloproteinase-7 expression

Research article

Prevention and treatment of acute radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials

Research article

Dose-volume histogram predictors of chronic gastrointestinal complications after radical hysterectomy and postoperative intensity modulated radiotherapy for early-stage cervical cancer

Research article

CUB Domain Containing Protein 1 (CDCP1) modulates adhesion and motility in colon cancer cells

Research article

Emerging markers of cachexia predict survival in cancer patients
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits