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KLF4 Improve Prognosis of Triple-negative Breast Cancer by Suppression of Epithelial-mesenchymal Transition

Takuya Nagata*, Katsuo Shimada, Lv Xiao Long, Tomoyuki Okumura, Kenichi Tazawa, Koichi Higashiyama, Tetsuro Shimzu and Takashi Ohnaga

Background: The prognostic value of KLF4 in triple negative breast cancer (TNBC) was described. Here we report an analysis of KLF4 expression in peripheral blood circulating tumor cells (CTCs) from patients with TNBC, which provided evidence that KLF4 negatively regulates the metastasis and growth of TNBC.

Method: We assessed the expression levels of KLF4 in 84 patients with TNBC by immunohistochemical staining and studied the patterns of metastasis/recurrence clinicopathologically. In addition, CTCs in the peripheral blood of TNBC patients were identified and compared with primary lesions in terms of KLF4 expression. Moreover, the expression of KLF4 was inhibited by transfecting cultured TNBC cells (MDA-MB231) with the small interfering RNA (siRNA) of KLF4 to analyze the effects of KLF4 on cell proliferation and epithelial-mesenchymal transition (EMT) -like changes.

Results: In the 84 patients with TNBC, higher KLF4 expression was associated with significantly better overall survival (OS) and disease-free survival (DFS). An analysis of KLF4 expression in CTCs of the TNBC patients showed that KLF4 expression was lower in CTCs than in cancer cells in primary lesions. TNBC cells (MDA-MB231) with inhibited KLF4 expression exhibited a greater ability to growth than controls. These cells also underwent EMT-like changes with reduced expression of epitherial factors such as E-cadherin. Treating these TNBC cells with eribulin resulted a reduction of the expression of stem cell/EMT markers.

Conclusion: TNBC patients with reduced KLF4 expression had poor outcomes. The results of our experiments suggest the expression of KLF4 is one of the important factors that inhibit the EMT and growth of TNBC.