乳腺癌相关基因GRHL1促进乳腺癌发生发展的机制研究

Breast cancer is the most common malignancy in women worldwide. Genetic susceptibility to breast cancer provides effective instruction for the medical intervention including preventive management, diagnosis, therapy and prognosis of the disease. Recent genome-wide association study identified 65 new loci that are associated with overall breast cancer risk. One possible affected gene among them is the Grainyhead like transcription factor 1(GRHL1). We found that the expression of GRHL1 is higher in breast carcinoma samples and various breast cancer cell lines. We showed that GRHL1 knockdown leads to decreased proliferation of MCF-7 and MDA-MB-231 cells, suggesting that GRHL1 is a potential breast cancer driver. We propose that GRHL1 binds to specific DNA binding sites, alters local chromatin configuration, and promotes ORC binding to origins and subsequent MCM complex recruitment, leading to the formation of pre-replication complex which represents the "licensing" step in the initiation of DNA replication. We hypothesize that GRHL1 promotes the proliferation of breast cancer cells through positively regulating the cell-type replication timing. Our research will not only provide evidence to support GRHL1 as a breast cancer-related gene, but also provide a mechanistic insight into the role of GRHL1 in promoting the breast carcinogenesis thus will benefit genetic risk prediction, family risk estimation, early screening, prevention and individualized therapy to breast cancer.

乳腺癌是危害妇女身体健康最常见的恶性肿瘤之一，乳腺癌基因易感性在乳腺癌预防、诊断、治疗及预后整个医疗干预过程发挥及其重要的指导作用。最近多国科学家合作的全基因组大规模测序研究鉴定出65个新的乳腺癌高风险突变位点，可能影响的基因之一是Grainyhead like转录因子GRHL1。我们的前期研究发现GRHL1能促进乳腺癌细胞生长增殖。我们推测GRHL1可能结合至复制起始点附近，介导局部染色质结构的改变，促进复制起始点识别蛋白ORC及解旋酶复合体MCM2-7的结合，从而促进DNA复制中的“许可”过程。GRHL1通过对乳腺癌细胞中DNA复制时间的正调节作用，最终促进乳腺癌细胞的生长增殖。我们的研究将不仅揭示GRHL1促进乳腺癌发生发展的的分子机制，同时也会为GRHL1作为乳腺癌相关的一个高风险基因提供实验证据，对乳腺癌风险预测、家族遗传相关风险评估、早期筛查与预防及个体精准化治疗有积极的意义。