title: WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.
abstract: Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. 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.
authors: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Peter
authors: P
authors: Wend
authors: Stephanie
authors: S
authors: Runke
authors: Korinna
authors: K
authors: Wend
authors: Brenda
authors: B
authors: Anchondo
authors: Maria
authors: M
authors: Yesayan
authors: Meghan
authors: M
authors: Jardon
authors: Natalie
authors: N
authors: Hardie
authors: Christoph
authors: C
authors: Loddenkemper
authors: Ilya
authors: I
authors: Ulasov
authors: Maciej S
authors: MS
authors: Lesniak
authors: Rebecca
authors: R
authors: Wolsky
authors: Laurent A
authors: LA
authors: Bentolila
authors: Stephen G
authors: SG
authors: Grant
authors: David
authors: D
authors: Elashoff
authors: Stephan
authors: S
authors: Lehr
authors: Jean J
authors: JJ
authors: Latimer
authors: Shikha
authors: S
authors: Bose
authors: Husain
authors: H
authors: Sattar
authors: Susan A
authors: SA
authors: Krum
authors: Gustavo A
authors: GA
authors: Miranda-Carboni
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011980:Receptors, Progesterone / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D025743:HMGA2 Protein; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D051153:Wnt Proteins; D051176:beta Catenin; C491119:WNT10B protein, human