ERK诱导的Mig-6磷酸化调控EGFR介导的乳腺癌增殖的作用机制研究

乳腺癌是女性高发的恶性肿瘤之一。EGF信号传导的异常与基底细胞样乳腺癌的不良预后密切相关。Mig-6作为EGF信号传导通路的负反馈抑制因子，能够抑制其下游传导通路的活性，进而抑制细胞增殖和肿瘤形成。我们的研究发现在EGF信号传导通路中，Mig-6能被ERK、Chk1等多个激酶在多个位点磷酸化，并已经证实EGF刺激能够通过PI3K/Akt/Chk1，使Mig-6 S251磷酸化，从而削弱Mig-6对细胞增殖的抑制功能；而ERK使Mig-6磷酸化的位点、功能和机制尚不明确。我们推断Mig-6不同位点的磷酸化都参与其功能的调节，通过多途径、多方向对EGF传导通路活性进行精确调节，从而保证细胞的正常增殖。本项目将干预ERK的表达及功能，研究其使Mig-6磷酸化、调节EGF信号传导活性和细胞增殖的机制；并通过动物模型和药物干预实验验证Mig-6磷酸化对乳腺癌增殖的调控，为乳腺癌治疗提供新的靶点。

Breast cancer is one of the most common malignant tumors among women. EGF signalling pathway is associated to the poor prognosis of basal-like breast cancer. As a negative feedback inhibitor of EGF signalling pathway, Mitogen inducible gene-6 (Mig-6) suppresses cell proliferation and tumorigenesis. Our original study demonstrated that Mig-6 could be phosphorylated by ERK and Chk1 kinases at different amino acid sites. Further study proved EGF treatment phosphorylated Mig-6 at Ser251 via the PI3K/Akt/Chk1 pathway, inhibited its negative regulation to cell proliferation. But the phosphorylation site of Mig-6 by ERK, and its function remain unclear. We speculate different phosphorylation sites of Mig-6 are all involved in the multifunctional modulation of EGF signalling pathway, resulting in exact cell growth. In this study, we aim to explore the function and mechanism of Mig-6 phosphorylation induced by ERK in EGF signalling pathway and proliferation of breast cancer cells, and furthermore, to prove the role of Mig-6 phosphorylation in breast cancer growth by animal experiment and anti-EGFR therapy. The result of this study would helpful in understanding the mechanism of breast cancer growth and exploring new treatment strategy for EGFR-positive breast cancer.