Open AccessRepurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth
Author(s) -
Thilakasiri Pathum,
Huynh Jennifer,
Poh Ashleigh R,
Tan Chin Wee,
Nero Tracy L,
Tran Kelly,
Parslow Adam C,
AfsharSterle Shoukat,
Baloyan David,
Hannan Natalie J,
Buchert Michael,
Scott Andrew Mark,
Griffin Michael DW,
Hollande Frederic,
Parker Michael W,
Putoczki Tracy L,
Ernst Matthias,
Chand Ashwini L
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809539
Subject(s) - cancer research , wnt signaling pathway , glycoprotein 130 , selective estrogen receptor modulator , cancer , tumor progression , estrogen receptor , medicine , signal transduction , biology , stat3 , microbiology and biotechnology , breast cancer
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 gp130 Y757F mice, where tumors arise exclusively through excessive gp130/ STAT 3 signaling in response to the IL 6 family cytokine IL 11. 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 IL 11‐dependent gp130/ STAT 3 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 IL 11‐dependent STAT 3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL 11 plays a tumor‐promoting role.