Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer
Open accessAbstract
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.
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Amyloid precursor protein is upregulated in advanced breast cancer and is associated with increased cancer cell proliferation, migration, and invasion.
“Amyloid precursor protein (APP), for example, is upregulated in advanced breast cancer and has been associated with increased cancer cell proliferation, migration, and invasion4.”
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- Authors
- Lim, S., Yoo, B. K., Kim, H.-S., Gilmore, H. L., Lee, Y., Lee, H.-P., Kim, S.-J., Letterio, J., & Lee, H.-G.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Virginia Commonwealth University (US)
- Case Western Reserve University (US)
- CHA University (KR)
- Rainbow Babies & Children's Hospital (US)
- Corresponding author
- Lim, Seunghwan
- Lee, Hyun-pil
- Lee, Hyoung-gon
- Venue
- BMC Cancer
- Published
- 2014-12
- Volume
- 14
- Issue
- 1
- Pages
- 928-928
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC4295427
- OpenAlex
- W2086492959
- Cited by
- 100
- References
- 54
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 6 · 2016: 6 · 2015: 1
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG028679)
- National Institute on Aging (AG028679, R01AG028679)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- amyloid precursor protein, breast cancer, metastasis, cell proliferation, cell migration and invasion, apoptosis, p27, caspase-3, Akt signaling, insulin-like growth factor I, GSK3β, FOXO1, chemosensitivity, TRAIL, 5-fluorouracil, therapeutic target
- MeSH terms
- Animals, Breast Neoplasms, Cell Movement, Cell Survival, Disease Models, Animal, Female, Humans, Insulin-Like Growth Factor I, Neoplasm Staging, Gene Expression, Amyloid beta-Protein Precursor, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27, Proto-Oncogene Proteins c-akt, Mice, Gene Knockdown Techniques
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