三苯氧胺促进雌激素受体ERα36阳性乳腺癌转移及其机制的研究

Most patients with estrogen receptor (ER)-positive breast cancer eventually fail to benefit from tamoxifen therapy, and usually accompanied with distant metastasis. Previous studies have revealed the correlation between ERα36, a variant of ERα, and tamoxifen resistance. We found inhere that ERα36 is correlated with tamoxifen-associated metastasis and poor prognosis in 1068 breast cancer patients of the breast cancer tissue bank in Southwest Hospital. Tamoxifen treatment is a detrimental factor for increased metastasis hazard ratio in ERα36 positive breast cancer patients. Mechanistically, tamoxifen functions as a potent ERα36 agonist not only to promote the growth and metastasis of ERα36+ cancer cells, but also to enrich cancer stem cells and corresponding to ALDH1A1 expression. This study indicates ERα36 as a novel independent metastasis marker and a potential therapeutic target, which should be examined for more precise diagnosis and effective design of endocrine treatment for breast cancer.

内分泌辅助治疗是雌激素受体阳性的乳腺癌患者的标准治疗方案，但多数患者由于耐药最终无法从三苯氧胺治疗中获益，并出现远处转移的现象。既往研究发现，ERα36（ERα的一个剪接体）与乳腺癌三苯氧胺耐药之间存在相关性。我们前期开发了新型ERα36单克隆抗体，对西南医院2006-2008年1068例乳腺癌标本进行免疫组化分析发现，ERα36表达与三苯氧胺相关的乳腺癌转移高度相关，三苯氧胺治疗明显增加了ERα36阳性乳腺癌的转移风险。体内外实验结果显示三苯氧胺作为ERα36激动剂，显著促进了ERα36阳性乳腺癌细胞的生长和转移。ERα36阳性乳腺癌细胞亚群显著富集乳腺癌干细胞，并且与ALDH1A1表达呈正相关。因此，研究ERα36参与三苯氧胺相关的乳腺癌转移的相关分子机制，对确定乳腺癌的转移标志物和潜在的治疗靶点具有重要意义，对探索乳腺癌个体化治疗方案具有重要价值。

本研究分析了雌激素受体亚型ERα36在乳腺癌的表达以及与乳腺癌内分泌治疗耐药与转移的相关性，研究了其在三苯氧胺相关的乳腺癌转移中的作用及分子机制。乳腺癌标本检测发现ERα36表达与三苯氧胺相关的乳腺癌转移相关，率先提出三苯氧胺促进ERα36阳性的乳腺癌进展和转移的观点。我们鉴定出ERα36在乳腺癌干细胞高表达，且具备转录活性，是潜在的逆转内分泌治疗抵抗的靶点。本研究为乳腺癌内分泌治疗抵抗研究提供了新视角，为ERα36靶向治疗提供重要依据。