染料木黄酮通过促进乳腺癌干细胞分化成熟逆转内分泌治疗耐药

We found soy isoflavone could improve the efficacy of aromatase inhibitor and alleviate endocrine therapy resistance. Recent researches showed that breast cancer stem cell was the main reason for endocrine therapy resistance. Meta analyses showed that Intake of soy isoflavone-rich food could reduce the risk of breast cancer, which may due to the differentiation and maturation of breast epithelium induced by genistein. In our preliminary study, genistein reduced the proportion of stem cells and increased the proportion of mature cells of endocrine therapy resistance breast cancer. Accordingly, we propose that the improved endocrine therapy resistance induced by genistein is closely related to the differentiation of breast cancer stem cells. This study will sort ER+ and ER- cell subsets by flow cytometry and co-culture with genistein and test in the endocrine therapy resistance breast cancer animal model we used previously. We will verify the paracrine effects of ER+ breast cancer cells regulated by genistein, and it would modify the self-renewal and differentiation signaling pathway and drive the direction of differentiation and maturation to facilitate the recovery of endocrine drug sensitivity. This study helps to solve the problem of endocrine therapy resistance in a new perspective. It will provide some theoretical and experimental foundation for the interaction between breast cancer cell subsets in drug resistance tumors and induction of differentiation therapy in breast cancer.

我们在前期项目中发现大豆异黄酮可提高芳香化酶抑制剂疗效，改善内分泌耐药现象。近年研究表明乳腺癌干细胞是乳腺癌患者内分泌治疗耐药的根本原因。Meta分析显示在幼年摄入富含大豆异黄酮的食物可降低女性成年后乳腺癌的发生风险，其机制与染料木黄酮诱导青春期前乳腺上皮分化成熟有关。我们预试验观察到染料木黄酮降低内分泌耐药乳腺肿瘤细胞的干细胞群比例，增加成熟细胞群比例。据此我们推测染料木黄酮改善内分泌耐药的机制与其诱导乳腺癌干细胞分化成熟密切相关。本研究将通过流式细胞分选ER+与ER-细胞亚群共培养和前期的内分泌耐药乳腺癌动物模型，验证染料木黄酮通过ER+乳腺癌细胞介导的旁分泌作用，调节乳腺癌干细胞的自我更新和分化通路，使其倾向于分化成熟的方向，进而恢复对内分泌药物的敏感性。本研究将从一个崭新的角度帮助解决乳腺癌内分泌耐药的难题，并为探索耐药乳腺癌细胞亚群间的相互作用和乳腺癌的诱导分化治疗奠定理论基础。

本课题组在前期项目中发现大豆异黄酮可提高芳香化酶抑制剂疗效，改善内分泌耐药现象。近年研究表明乳腺癌干细胞是乳腺癌患者内分泌治疗耐药的根本原因。Meta 分析显示在幼年摄入富含大豆异黄酮的食物可降低女性成年后乳腺癌的发生风险，其机制与染料木黄酮诱导青春期前乳腺上皮分化成熟有关。据此我们推测染料木黄酮改善内分泌耐药的机制与其诱导乳腺癌干细胞分化成熟密切相关。本研究通过通过ER+与ER-细胞亚群共培养和内分泌耐药乳腺癌动物模型，验证了染料木黄酮通过ER+乳腺癌细胞介导的旁分泌作用，调节乳腺癌干细胞的自我更新和分化通路，使其倾向于分化成熟的方向，进而恢复对内分泌药物的敏感性。本研究经实验证实了染料木黄酮通过旁分泌机制促进乳腺癌干细胞分化成熟，改善芳香化酶抑制剂耐药，从新的角度帮助解决乳腺癌内分泌耐药的难题。