WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.
Bottom Line: Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation.We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells.Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.
Affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.Show MeSH
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Mentions: To determine how well our novel MMTV-Wnt10b-IRES-LacZ (Wnt10bLacZ) mouse model resembles human TNBC, we conducted IHC for estrogen receptor-alpha (ERα), progesterone receptor (PR) and HER2 protein expression levels (Fig 2A). Wnt10b-driven tumours are phenotypically like human TNBC—devoid of ERα, PR and HER2. In contrast, ERα and PR protein expression, in the uterus of wild-type female mice, is present in various subpopulations of myoepithelial, stromal cells and both luminal and glandular epithelial cells (Fig 2A). Interestingly, the Wnt10b tumorigenic mouse model contrasts the MMTV-Wnt1 model, in part, because Wnt1-driven tumours have been reported to express hormone receptors (Teissedre et al, 2009). HER2 protein expression is very high in mouse MMTV-neu2/ErbB2 (ErbB2TG) tumours but not expressed at all in the Wnt10bLacZ tumours. Furthermore, Wnt10b-driven tumours express the basal-epithelial markers CK5 and CK6, in contrast to ErbB2TG tumours (Supporting Information Fig S2A–C). We also show that Wnt10bLacZ-driven tumours express high levels of β-galactosidase activity, have transcriptionally active nuclear β-catenin and correlating with high levels of AXIN2 protein expression (Supporting Information Fig S2D–F).
Affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.