Abstract
BackgroundAmyloid-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.MethodsThe 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.ResultsWe 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.ConclusionThe 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.
Highlights
Amyloid-β precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease
The level of APP expression is linked to malignancy of breast cancer cells In order to investigate the correlation between APP expression and malignancy of breast cancer, the expression level of APP was examined in a series of human and mouse breast cancers with increasing malignancy
The four human breast cancer cell lines MCF10A1 (M-I), MCF10AT1k.cl2 (M-II), MCF10CA1h (M-III), and MCF10CA1a.cl1 (M-IV) were used in which malignant breast epithelial cells (M-I) cells are spontaneously immortalized from normal breast epithelial cells whereas M-II, MIII, and M-IV cells are derived from M-I cells transformed with Ha-Ras oncogene [22,23]
Summary
Amyloid-β precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. It has been reported that APP is linked to proliferation of thyroid epithelial cells and epidermal basal cell proliferation [8,9,10,11] and, interestingly, the increased expression of APP in several types of cancers including pancreatic, lung, colon and breast cancer has been reported [10,11,12,13,14,15] These studies suggested that APP has growthpromoting effect as an autocrine growth factor while the underlying mechanism in the regulation of cellular signaling and gene expression has not been fully explored. The potential role of APP in cancer cell motility is supported by studies which show APP plays a role in migration of neuronal precursor cells and neurite outgrowth [16,17]
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