Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/20520
Title: Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth.
Austin Authors: Thilakasiri, Pathum;Huynh, Jennifer;Poh, Ashleigh R;Tan, Chin Wee;Nero, Tracy L;Tran, Kelly;Parslow, Adam C;Afshar-Sterle, Shoukat ;Baloyan, David;Hannan, Natalie J;Buchert, Michael;Scott, Andrew M ;Griffin, Michael D W;Hollande, Frederic;Parker, Michael W;Putoczki, Tracy L;Ernst, Matthias ;Chand, Ashwini L 
Affiliation: Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
ACRF Rational Drug Discovery Centre, St Vincent's Institute, Melbourne, Victoria, Australia
Department of Clinical Pathology, University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia
Issue Date: Apr-2019
metadata.dc.date: 2019-03-18
Publication information: EMBO molecular medicine 2019; 11(4): e9539
Abstract: Excessive signaling through gp130, the shared receptor for the interleukin (IL)6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Here, we established the in vivo utility of bazedoxifene, a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130-dependent tumor growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumor burden in gp130Y757F mice, where tumors arise exclusively through excessive gp130/STAT3 signaling in response to the IL6 family cytokine IL11. Likewise, in mouse models of sporadic colon and intestinal cancers, which arise from oncogenic mutations in the tumor suppressor gene Apc and the associated β-catenin/canonical WNT pathway, bazedoxifene treatment reduces tumor burden. Consistent with the proposed orthogonal tumor-promoting activity of IL11-dependent gp130/STAT3 signaling, tumors of bazedoxifene-treated Apc-mutant mice retain excessive nuclear accumulation of β-catenin and aberrant WNT pathway activation. Likewise, bazedoxifene treatment of human colon cancer cells harboring mutant APC did not reduce aberrant canonical WNT signaling, but suppressed IL11-dependent STAT3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL11 plays a tumor-promoting role.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20520
DOI: 10.15252/emmm.201809539
ORCID: 0000-0002-6399-1177
0000-0002-1245-729X
0000-0002-6656-295X
PubMed URL: 30885958
Type: Journal Article
Subjects: colon cancer
gastric cancer
gp130
interleukin‐11
interleukin‐6
Appears in Collections:Journal articles

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