染色体重塑蛋白MORC2在乳腺癌进展及抗雌激素治疗敏感性中的作用及其分子机制研究

Breast cancer progression and therapeutic resistance are mojor challenges in the management of breast cancer patients in clinic,but the underlying mechanisms remain largely unknown. Our previous study demonstrated that MORC2 is a novel chromatin remodeling factor that promotes DNA damage repair and cell survival following DNA damage.However, whether MORC2 is involved in tumorigenesis and cancer progression is not known so far. Using bioinformatic methods, we found that MORC2 is a potential downstream target gene of the estrogen (E2)-estrogen recepotr (ER) signaling axis, and that the levels of MORC2 gene expression are signficantly assocaited with survival and therapeutic resistance in patients with breast cancer. Based on our own findings and preliminary data, in the present study we aim to address the functional roles and underlying mechanisms for MORC2 in breast cancer progression and therapeutic resistance using multiple in vitro and in vivo experimental models. The key questions to be addressed in this study include how the E2-ER signaling axis regulates MORC2 expression, whether and how MORC2 plays a critical role in breast cancer progression and cellular sensitivity to anti-estrogen therapy. The expected findings from this study will provide a breakthrough or basis for discovering new methods as well as strategies for inhibiting cancer progression and resoring cellular sensitivity to anti-estrogen therapy in patients with breast cancer. Taken together, in the light of the solid research background and preliminary data, we strongly believe that this study is definitely feasible, novel, and innovative and has the potential clinical translation implications.

乳腺癌进展及治疗耐药的分子机制是目前乳腺癌研究领域有待解决的关键科学问题之一。我们前期工作显示，染色体重塑蛋白MORC2能促进DNA损伤修复及损伤后细胞存活，但是否MORC2表达与肿瘤发生、发展有关目前尚不清楚。通过生物信息学方法分析发现，MORC2是一个潜在的雌激素(E2)-雌激素受体(ER)信号下游的关键分子，与乳腺癌病人的存活及内分泌治疗耐药潜在相关。本研究立足于前期工作的基础上，拟采用多种体内、外实验模型，系统深入地来解读MORC2蛋白与乳腺癌进展及治疗耐药的关系及其分子机制。拟解决的关键问题包括E2-ER信号轴对MORC2表达的影响及其分子机制，以及MORC2表达在乳腺癌进展及抗雌激素治疗敏感性中的关键作用及分子机制。本研究成果将为发现新的抑制乳腺癌进展及逆转抗雌激素耐药的方法和措施提供重要的理论基础。本研究具有扎实的研究背景和基础，具有可行性、创新性和重要的临床转化应用价值。

乳腺癌进展及治疗耐药的分子机制是目前乳腺癌研究领域有待解决的关键科学问题之一。我们前期工作显示，染色体重塑蛋白MORC2能促进DNA损伤修复及损伤后细胞存活，但是否MORC2表达与肿瘤发生、发展有关目前尚不清楚。该项目主要研究MORC2蛋白在乳腺癌内分泌治疗耐药及侵袭转移过程中的作用及其分子机制。我们研究发现：1）雌激素以及抗雌激素药物他莫昔芬以及氟维司琼增加MORC2蛋白稳定性。其分子机制是雌激素、他莫昔芬以及氟维司琼通过G蛋白偶联雌激素受体1(GPER1)激活蛋白激酶 A (protein kinase A，PKA)。反过来PKA促进MORC2蛋白582位酪氨酸的磷酸化，从而保护MORC2被细胞自噬通路降解；2）细胞功能以及临床数据证实MORC2蛋白介导雌激素刺激的乳腺癌细胞增殖以及内分泌治疗耐药；3）MORC2蛋白通过其脯氨酸结构域 (PRD)与细胞粘附蛋白CTNND1结合促进乳腺癌侵袭转移；4）MORC2蛋白276位甲硫氨酸突变为异亮氨酸（M276I）促进乳腺癌侵袭转移，其作用机制是M276I突变增加MORC2与异源核核糖核蛋白M（hnRNPM）的结合能力，从而促进CD44基因可变剪切和上皮 - 间质转化（EMT）。本研究成果将为发现新的抑制乳腺癌进展及逆转抗雌激素耐药的方法和措施提供重要的理论基础。