Loss of WIF-1 and Wnt5a expression is related to aggressiveness of sporadic breast cancer in Tunisian patients

Trifa, Fatma; Karray-Chouayekh, Sondes; Jmal, Emna; Jmaa, Zeineb Ben; Khabir, Abdelmajid; Sellami‐Boudawara, Tahya; Frikha, M.; Daoud, J.; Mokdad-Gargouri, Raja

doi:10.1007/s13277-013-0694-2

Cited by 22 publications

(17 citation statements)

References 41 publications

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“…In patients with ER-negative disease, lower levels of WNT5A are significantly associated with worse clinical outcome. These results are in accordance with those of Trifa et al in Tunisian patients [22]. …”

Section: Expression and Function Of Wnt5a In Breast Cancersupporting

confidence: 93%

Multiple Roles of WNT5A in Breast Cancer

et al. 2016

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Breast cancer is one of the most common malignant tumors of women. Modern combinatorial therapeutic regimens can reduce patient tumor burdens to undetectable levels, yet in many cases these tumors will relapse. Understanding of breast cancer biology, developing more potent therapeutic approaches, and overcoming resistance are of great importance. WNT5A is a non-canonical signaling member of the WNT family. Its role in breast cancer still remains unclear. Most of the evidence shows that WNT5A is a suppressor in breast cancer and loss of its expression is associated with poor prognosis, while some evidence suggests the tumorigenicity of WNT5A. WNT signaling molecules are potent targets for treatment of cancer. Therefore, understanding the role of WNT5A in breast cancer may provide new ideas and methods for breast cancer treatment. We review the evidence concerning WNT5A and breast cancer involving the signaling pathways and the molecular-targeted therapy of WNT5A. Our results show that the role WNT5A plays depends on the availability of key receptors and intercellular interactions among different cell types.

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Section: Expression and Function Of Wnt5a In Breast Cancersupporting

confidence: 93%

Multiple Roles of WNT5A in Breast Cancer

et al. 2016

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“…However, the manner in which WNT signaling pathways and their inhibitors function together during cancer progression remains unclear. Whereas APCDD1 expression is negatively associated with invasion, WIF, DKK and SFRP are epigenetically inactivated in breast cancer cells, independent of invasion (28,29). Therefore, different WNT signaling pathway inhibitors may serve crucial functions in the multiple roles of the canonical WNT signaling pathway in breast cancer progression.…”

Section: Discussionmentioning

confidence: 99%

APC downregulated 1 inhibits breast cancer cell invasion by inhibiting the canonical WNT signaling pathway

Cho

2017

Oncology Letters

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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...

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“…21 Others have shown that WIF1 promoter hypermethylation correlates with loss of p53 expression. 60 p53 has been shown to regulate the expression of Wnt genes and suppress the Wnt/ β -catenin signaling. 61, 62 Our data suggest for the first time the existence of a positive feedback by which WIF1 regulates the expression of p53.…”

Section: Discussionmentioning

confidence: 99%

Wnt inhibitory factor 1 suppresses cancer stemness and induces cellular senescence

et al. 2014

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Hyperactivation of the Wingless-type (Wnt)/β-catenin pathway promotes tumor initiation, tumor growth and metastasis in various tissues. Although there is evidence for the involvement of Wnt/β-catenin pathway activation in salivary gland tumors, the precise mechanisms are unknown. Here we report for the first time that downregulation of the Wnt inhibitory factor 1 (WIF1) is a widespread event in salivary gland carcinoma ex-pleomorphic adenoma (CaExPA). We also show that WIF1 downregulation occurs in the CaExPA precursor lesion pleomorphic adenoma (PA) and indicates a higher risk of progression from benign to malignant tumor. Our results demonstrate that diverse mechanisms including WIF1 promoter hypermethylation and loss of heterozygosity contribute to WIF1 downregulation in human salivary gland tumors. In accordance with a crucial role in suppressing salivary gland tumor progression, WIF1 re-expression in salivary gland tumor cells inhibited cell proliferation, induced more differentiated phenotype and promoted cellular senescence, possibly through upregulation of tumor-suppressor genes, such as p53 and p21. Most importantly, WIF1 significantly diminished the number of salivary gland cancer stem cells and the anchorage-independent cell growth. Consistent with this observation, WIF1 caused a reduction in the expression of pluripotency and stemness markers (OCT4 and c-MYC), as well as adult stem cell self-renewal and multi-lineage differentiation markers, such as WNT3A, TCF4, c-KIT and MYB. Furthermore, WIF1 significantly increased the expression of microRNAs pri-let-7a and pri-miR-200c, negative regulators of stemness and cancer progression. In addition, we show that WIF1 functions as a positive regulator of miR-200c, leading to downregulation of BMI1, ZEB1 and ZEB2, with a consequent increase in downstream targets such as E-cadherin. Our study emphasizes the prognostic and therapeutic potential of WIF1 in human salivary gland CaExPA. Moreover, our findings demonstrate a novel mechanism by which WIF1 regulates cancer stemness and senescence, which might have major implications in the field of cancer biology.

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Loss of WIF-1 and Wnt5a expression is related to aggressiveness of sporadic breast cancer in Tunisian patients

Cited by 22 publications

References 41 publications

Multiple Roles of WNT5A in Breast Cancer

Multiple Roles of WNT5A in Breast Cancer

APC downregulated 1 inhibits breast cancer cell invasion by inhibiting the canonical WNT signaling pathway

Wnt inhibitory factor 1 suppresses cancer stemness and induces cellular senescence

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