Abstract. Canonical WNT signaling promotes breast cancer progression. Although APC downregulated 1 (APCDD1) may inhibit canonical WNT signaling, its role in breast cancer remains to be fully understood. The present study demonstrated that APCDD1 suppressed in vitro breast cancer growth and metastasis by inhibiting canonical WNT signaling. The present study demonstrated that APCDD1 expression was negatively associated with breast cancer cell invasion, which was consistent with previous studies that indicated that APCDD1 expression was decreased in invasive ductal carcinoma compared with that in ductal carcinoma in situ. Furthermore, APCDD1 expression was negatively associated with nuclear β-catenin expression and transcription factor/lymphoid enhancer binding factor 1 transcriptional activity in the present study. Silencing APCDD1 in non-invasive breast cancer cells using lentiviral APCDD1 short hairpin RNAs enhanced migration and invasion, which may be mediated by canonical WNT signaling, whereas the overexpression of human influenza hemagglutinin-tagged APCDD1 in invasive breast cancer cells repressed these properties. Therefore, the present study suggested that APCDD1 regulated breast cancer progression by targeting canonical WNT signaling and modulating breast cancer cell invasion.
IntroductionThe WNT signaling pathway is associated with numerous biological events, including embryonic development and adult tissue homeostasis. Therefore, abnormal WNT signaling is associated with diseases, including certain types of cancer (1,2). WNTs activate the canonical and non-canonical signaling pathways, which are mutually exclusive. The canonical WNT signaling pathway triggers β-catenin-dependent transcriptional regulation, whereas the non-canonical WNT signaling pathway activates the β-catenin-independent signaling pathway (1,2).The canonical WNT signaling pathway regulates normal breast development, and its deregulation is associated with breast cancer progression (3,4). WNTs aid in the generation of the canonical WNT signaling pathway by binding to the coreceptors LDL receptor-related protein (LRP)5/6 and frizzled on the cell surface, and activating the β-catenin/t-cell factor (TCF) complex (2). Overexpression of Wnt1, which may be induced by the integration of the mouse mammary tumor virus, triggers mammary tumor development (5,6). Autocrine WNT signaling regulates mammary epithelial cell fate by regulating renewal and the epithelial-to-mesenchymal transition (EMT), thereby affecting tumorigenesis and metastasis in a deregulated signaling state (7,8). Accordingly, the WNT-activated β-catenin/TCF complex potentiates breast cancer metastasis by altering the expression of genes associated with EMT (9,10).Previous studies have revealed multiple inhibitors of the canonical WNT signaling pathway, including secreted frizzled-related protein (SFRP), dickkopf (DKK), and WNT inhibitory factor (WIF) (2,11). In addition, APC downregulated 1 (APCDD1) may inhibit the canonical WNT signaling pathway by directly binding WNT3A and L...