The Wilms’ tumor suppressor WT1 induces estrogen-independent growth and anti-estrogen insensitivity in ER-positive breast cancer MCF7 cells

摘要

A switch from estrogen-dependent to estrogen-independent growth is a critical step in malignant progression of breast cancer and is a major problem in endocrine therapy. However, the molecular mechanisms underlying this switch remain poorly understood. The Wilms’ tumor suppressor gene, wt1, encodes a zinc finger protein WT1 that functions as a transcription regulator. High levels of the WT1 expression have been associated with malignancy of breast cancer. The goal of this study was to investigate the function of WT1 in malignant progression of breast cancer. We found that the high passage ER-positive breast cancer MCF7^H cells expressed EGFR, HER2 and WT1 at higher levels compared to the low passage MCF7^L cells. MCF7^H cells responded weakly to estrogen stimulation, grew rapidly in the absence of estrogen and were insensitive to anti-estrogens such as ICI 182,780 and 4-hydroxy-tamoxifen (4OH-TAM). We also established stable cell lines from the low passage MCF7^L cells to constitutively express exogenous WT1 and found elevated levels of EGFR and HER2 expression, estrogen-independent growth and anti-estrogen insensitivity in WT1-transfected MCF7^L cells. These results suggested WT1 promotes estrogen-independent growth and anti-estrogen resistance in ER-positive breast cancer cells presumably through activation of the signaling pathways mediated by the members of EGFR family.