In addition, we found using Bayesian network-based machine learning that 30 NRF1 motif-enriched genes including growth factor receptors-FGFR1, IGF1R; E2Fs transcription factor family-E2F1, E2F3; MAPK pathway-SHC2, GRB2, MAPK1; PI3K-AKT-mTOR signaling pathway-PIK3CD, PIK3R1, PIK3R3, RPS6KB2; WNT signaling pathway-WNT7B, DLV1, DLV2, GSK3B, NRF1, and DDB2, known for its role in DNA repair and involvement in early events associated with metastatic progression of breast cancer cells, were associated with HER2-amplified breast cancer.
Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGFβ-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process.
Our results indicate that several of the Wnt ligands, especially Wnt1 and Wnt6, are strongly expressed in both normal and malignant breast tissue and that Wnt7b is down-regulated in breast cancer, compared to normal breast epithelium.