LEF1在乳癌中藉由調控ERα促進其腫瘤生長

Abstract

雌性激素受體(ER)在人類乳癌中扮演極重要的角色。LEF1是調控Wnt/β-catenin路徑的轉錄因子，然而，其對於癌症的調控機制尚未清楚。根據組織免疫染色的結果，我們發現LEF1通常表現於婦科疾病之相關腫瘤且在乳癌中其表現與ER相關。乳癌與卵巢癌細胞株在給予estradiol(E2)處理後會誘導LEF1的表現。當另外又施予ER抑制劑Tamoxifen後則將抑制其表現。欲進一步探討 ER與LEF1路徑之間的關係，我們利用shRNA敲減LEF1，發現ER的表現量也大幅降低。細胞增生率分析和細胞培養軟瓊脂膠試驗更證實了LEF1對於ER陽性乳癌細胞株的生長是必要的，而ER陰性的乳癌細胞株的生長則不受到LEF1的影響。除此之外，我們也發現為ER所調控的基因PR和GREB1會因LEF1被敲減而有表現量減少的現象。我們的研究顯示，LEF1可藉由調控ER路徑進而影響ER陽性之乳癌的增生。

Estrogen receptor-alpha (ERα) is a key factor in the development of breast cancer in human. Lymphoid-enhancing factor 1 (LEF1) is a transcription factor mediating Wnt/β-catenin signaling. However, the role of LEF1 in cancer is still poorly characterized. By immunohistochemistry, we found that LEF1 is frequently expressed in tumors of female genital organs and expression of LEF1 is strongly associated with ER positivity in breast cancer. Treatment of the breast cancer and ovarian cancer cell lines with estradiol (E2) induced LEF1 expression. The induction was abolished by treatment with ER inhibitor tamoxifen. To further elucidate the relationship between ER and LEF1 pathways, we knocked down the expression of LEF1 by shRNA in MCF7 cells and found the expression of ER is dramatically reduced. Using MTT assay and soft agar colony forming assay, we found LEF1 is essential for the growth of ER-positive breast cancer cell lines, whereas the growth of ER-negative breast cancer cell lines was not affected by knockdown of LEF1. In addition, we found the expression levels of estrogen-responsive genes, PR and GREB1, were reduced by knockdown of LEF1. Our study suggests LEF1 is essential for proliferation of ER-positive breast cancer by regulate ER pathway.