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.

β-Catenin Signaling Is a Critical Event in ErbB2-Mediated Mammary Tumor Progression

“…Taken together, the strong reduction of ERBB2 expression observed upon ablation of b-catenin activity either through RNA interference or IGC-001 is due to a disruption of the ERRa/b-catenin/CBP-dependent recruitment of RNA polymerase II to an intronic ERBB2 site that regulates ERBB2 transcription. Consistent with these data, it has been previously shown that ICG-001 specifically interferes with the ability of b-catenin to form complexes with CBP and Lef1 (54). The ICG-001-dependent reduction in GRB7 transcription can also be attributed to the fact that the proximal promoters of GRB7 and other ERBB2 amplicon components are also regulated by these b-catenin-containing complexes ( Supplementary Fig.…”

Caveolin 1 knockdown inhibits the proliferation, migration and invasion of human breast cancer BT474 cells

“…2A) associated with decreased cyclin D1 expression, and increased G0/G1 phase population and reduced S phase population. Furthermore, c-Fos, as well as β-catenin, has previously been demonstrated to function as a nuclear transcription factor (23,24). In addition, in the present study, their expression was found to be decreased by caveolin 1 knockdown in BT474 cells (Fig.…”

Interplay between microRNAs and WNT/β-catenin signalling pathway regulates epithelial–mesenchymal transition in cancer

“…For example, familial adenomatous polyposis (FAP) patients carry a mutated germline APC, which is unable to suppress b-catenin accumulation and promotes colorectal carcinomas (CRC) in the context of mutated KRAS and P53 [20,21]. Moreover, overexpression of WNT3A and WNT10B is positively associated with the development of breast cancers [22]. Mutations in the b-catenin gene, CTNNB1 are prevalent in many cancers such as those of hepatocellular, gastric, pancreas, ovarian and endometrial malignances [23].…”