Mammary Tumor Regression Elicited by Wnt Signaling Inhibitor Requires IGFBP5

Liu, Bob Y.; Soloviev, Irina; Huang, Xiao-Dong; Chang, Peter Mu Hsin; Ernst, James A.; Polakis, Paul; Sakanaka, Chie

doi:10.1158/0008-5472.can-11-3668

Cited by 25 publications

(24 citation statements)

References 32 publications

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“…LRP6 antagonist Mesd/Mesd peptide or LRP6 antagonistic antibodies also inactivate the Wnt/β‐catenin pathway and suppress MMTV‐ Wnt1 tumor growth . Similar effects were observed in MMTV‐ Wnt1 tumors treated with a soluble Wnt Receptor Frizzled8 CRD‐hFc . Moreover, FZD7 antibody was shown to block the canonical Wnt pathway and suppress breast cancer cell growth in human tumor xenograft .…”

Section: Wnt Ligands/receptors May Be Targets For Breast Cancermentioning

confidence: 69%

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

et al. 2018

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Wnt proteins, a group of secreted glycoproteins, mainly combine with receptors Frizzled (FZD) and/or low‐density‐lipoprotein receptor‐related proteins 5/6 (LRP5/6), initiating β‐catenin‐dependent and ‐independent signaling pathways. These pathways, which can be regulated by some secreted antagonists such as secreted Frizzled‐related proteins (SFRP) and dickkopf‐related protein (DKK), play a critical role in embryo development and adult homeostasis. Overactivation of Wnt signaling has been implicated in some human diseases including cancer. Wnt transgenic mice provide convincing evidence that Wnt signaling is involved in breast cancer initiation and progression, which is further strengthened by observations on human clinical breast cancer patients and studies on in vitro cultured human breast cancer cells. This review focuses on the roles of Wnt ligands, receptors and antagonists in breast cancer development instead of molecules or signaling transactivating β‐catenin independent on Wnt upstream components.

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Section: Wnt Ligands/receptors May Be Targets For Breast Cancermentioning

confidence: 69%

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

et al. 2018

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“…Thus, 7 of 10 cell lines showed DVLi-induced ERK activation, and in each, DVLi enhanced response to IGFIR inhibition. Supporting the existence of functional cross-talk between the IGF axis and proximal WNT components, upregulation of IGF-binding protein 5 was shown to mediate growth inhibitory effects of a soluble Wnt inhibitor in murine MMTV-Wnt1-driven tumors (36). Therefore, to test the potential clinical relevance of our findings, we evaluated IGFIR and DVL inhibition in mice bearing DU145 prostate cancer xenografts.…”

Section: Proximal Wnt Inhibition Mimics Effects Of Dvl3 Depletionmentioning

confidence: 86%

“…Although the DVLi we used has relatively low potency, the WNT pathway is an intense focus for drug development (34,36), offering the prospect of more potent inhibitors in future. Therefore, we used this DVLi to perform proof-of- Figure 4.…”

Section: Proximal Wnt Inhibition Mimics Effects Of Dvl3 Depletionmentioning

confidence: 99%

Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling

et al. 2014

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Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK-ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor-bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc-Grb2-SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition. Cancer Res; 74(20); 5866-77. Ó2014 AACR.

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“…IGFBP5 is the most conserved member of the IGFBPs family and is frequently deregulated in human malignancies such as neuroblastoma [25], osteosarcoma [27, 38], breast [26, 39, 40] as well as head and neck squamous cell carcinoma [41]. IGFBP5 modulates cellular functions either in an IGF-dependent manner through IGF1R signaling or in an IGF-independent manner [42].…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

et al. 2016

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Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo. Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells. Selinexor also significantly decreased cell proliferation as well as induced cell cycle arrest and apoptosis of liposarcoma cells. The drug also significantly decreased tumor volumes and weights of liposarcoma xenografts. Importantly, selinexor inhibited insulin-like growth factor 1 (IGF1) activation of IGF-1R/AKT pathway through upregulation of insulin-like growth factor binding protein 5 (IGFBP5). Further, overexpression and knockdown experiments showed that IGFBP5 acts as a tumor suppressor and its expression was restored upon selinexor treatment of liposarcoma cells. Selinexor decreased aurora kinase A and B levels in these cells and inhibitors of these kinases suppressed the growth of the liposarcoma cells. Overall, our study showed that selinexor treatment restored tumor suppressive function of IGFBP5 and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer.

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Mammary Tumor Regression Elicited by Wnt Signaling Inhibitor Requires IGFBP5

Cited by 25 publications

References 32 publications

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

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

Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling

Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

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