Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

Yin, Ping; Wang, Wei; Zhang, Zhongbo; Bai, Yu; Gao, Jian; Zhao, Chenghai

doi:10.1111/cas.13771

Cited by 81 publications

(56 citation statements)

References 76 publications

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“…In agreement with the above findings, the pathway analysis of the gene expression data in this study showed enrichment of WNT (both canonical and non-canonical) pathways, the planar cell polarity (PCP) pathway, and signaling pathways regulating the pluripotency of stem cells in DCIS (generally induced by WNT signaling). The Wnt signaling pathway is known to promote cancer progression, metastasis, and is involved in EMT [48]. EMT is essential in tumor invasion because it reduces cell-cell adhesion and increases cell motility.…”

Section: Discussionmentioning

confidence: 99%

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Mohammed

Utturkar

Lee

et al. 2020

Cancers

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The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early molecular events in breast cancer progression and development. Transcriptomic studies along the continuum of cancer progression in the mammary gland from healthy, through atypical ductal hyperplasia (ADH), DCIS, and invasive carcinoma were performed using the canine model. Gene expression profiles of preinvasive DCIS lesions closely resemble those of invasive carcinoma. However, certain genes, such as SFRP2, FZD2, STK31, and LALBA, were over-expressed in DCIS compared to invasive cancer. The over-representation of myoepithelial markers, epithelial-mesenchymal transition (EMT), canonical Wnt signaling components, and other pathways induced by Wnt family members distinguishes DCIS from invasive. The information gained may help in stratifying DCIS as well as identify actionable targets for primary and tertiary prevention or targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Mohammed

Utturkar

Lee

et al. 2020

Cancers

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“…MMTV-Wnt1, MMTV-Wnt10b and MMTV-βcatΔN transgenic mice have clearly demonstrated that canonical Wnt/β-catenin pathway has the capacity to induce BC development [22]. In human BC, Wnt10b, but not Wnt1, as well as Fzd7 and Wnt co-receptor LDL receptor-related proteins 6 (LRP6) was overexpressed in TNBC, with activation of β-catenin pathway [7,[23][24][25].…”

Section: Discussionmentioning

confidence: 99%

Non-canonical Fzd7 signaling contributes to breast cancer mesenchymal-like stemness involving Col6a1

et al. 2020

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Mesenchymal-like stemness is characterized by epithelial-mesenchymal transition (EMT). Breast cancer (BC) cell mesenchymal-like stemness is responsible for distal lung metastasis. Interrogation of databases showed that Fzd7 was closely associated with a panel of mesenchymal-related genes and a panel of stemness-related genes. Fzd7 knockdown in mesenchymal-like MDA-MB-231 and Hs578T cells reduced expression of Vimentin, Slug and Zeb1, induced an epithelial-like morphology, inhibited cell motility, impaired mammosphere formation and decreased Lgr5+ subpopulation. In contrast, Fzd7 overexpression in MCF7 cells resulted in opposite changes. Fzd7 knockdown delayed xenograft tumor formation, suppressed tumor growth, and impaired lung metastasis. Mechanistically, Fzd7 combined with Wnt5a/b and modulated expression of phosphorylated Stat3 (p-STAT3), Smad3 and Yes-associated protein 1 (Yap1). Moreover, Fzd7-Wnt5b modulated expression of collagen, type VI, alpha 1 (Col6a1). Both Wnt5b knockdown and Col6a1 knockdown disrupted BC cell mesenchymal phenotype and stemness. Taken together, Fzd7 contributes to BC cell EMT and stemness, inducing tumorigenesis and metastasis, mainly through a non-canonical Wnt5b pathway. Col6a1 is implicated in Fzd7-Wnt5b signaling, and mediates Fzd7-Wnt5b -induced mesenchymal-like stemness.

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“…The Wnt pathway is one of the most important pathways regulating the development of breast cancer [43], andβ-catenin is a key regulator of the Wnt pathway. This pathway is not active in normal mature cells.…”

Section: Discussionmentioning

confidence: 99%

VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, induces cell cycle arrest and apoptosis in breast cancer cells by inhibiting the Wnt/β-catenin pathway

Dang

Tai

et al. 2020

Preprint

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Background: Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects. In this study, we investigated the cytotoxic and apoptotic effects of VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, on human breast cancer cells and the possible underlying mechanisms.Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test was used to observe the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells induced on VALD-3. The effects of VALD-3 on the cell cycle were analyzed in MCF-7 and MDA-MB-231 cells by PI single staining. Hoechst 33258 staining was performed to determine if VALD-3 induced apoptosis of MCF-7 and MDA-MB-231 cells and Annexin V/PI staining was performed to quantify the percentages of apoptosis. The expression of pro-apoptotic proteins and anti-apoptotic proteins in MCF-7 and MDA-MB-231 cells was investigated by Western blotting. Wnt/β-catenin signaling pathways were also examined. The antitumor activity and survival analysis of VALD-3 in vivo was determined by the nude mice xenograft assay.Results: Flow cytometry analysis showed that VALD-3 triggered cell cycle arrest and induced apoptosis of breast cancer cells. Western blot analysis revealed that VALD-3 upregulated pro-apoptotic proteins (Bad and Bax), downregulated anti-apoptotic proteins (Bcl-2, Bcl-xl, survivin and XIAP) and increased the expression of cleaved caspase-3, cleaved caspase-8, Cyto-c and cleaved PARP. VALD-3 also regulated the Wnt/β-catenin signaling pathway in breast cancer cells, inhibiting the activation of downstream molecules. By xenografting human breast cancer cells into nude mice, we found that VALD-3 significantly suppressed tumor cell growth while showing low toxicity against major organs. In addition, survival analysis results showed that VALD-3 can significantly prolong the survival time of mice (P=0.036).Conclusion: This study is the first to show that VALD-3 induces apoptosis and cell cycle arrest in human breast cancer cells by suppressing Wnt/β-catenin signaling, indicating that it could be a potential drug for the treatment of breast cancer.

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Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

Cited by 81 publications

References 76 publications

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer

Non-canonical Fzd7 signaling contributes to breast cancer mesenchymal-like stemness involving Col6a1

VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, induces cell cycle arrest and apoptosis in breast cancer cells by inhibiting the Wnt/β-catenin pathway

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