Bcl-2及自噬在三阴性乳腺癌中的调控作用探讨

Breast cancer is the most frequent type of cancer in women worldwide, with an incidence that rises dramatically with age. Triple-negative breast cancer (TNBC) subtype accounts for 12-17% of breast cancer, characterized by the lack of ER/PR/HER2 expression, displays drug tolerance. To date, not a single targeted therapy has been approved for the treatment of TNBC and cytotoxic chemotherapy remains the standard treatment, about 1/3 of the TNBC patients show resistance to chemotherapy. Therefore, elucidation of the molecular mechanism underlying the TNBC regulation holds promise for the targeted therapy. Dis-regulation of Bcl-2, autophagy or mitochondrial function was found closely related to breast cancer, however, the roles they play in TNBC and the cross-talk among these pathways remain unclear. Our preliminary data demonstrated that the expression of Bcl-2 and autophagy level in TNBC were significantly lower than that in the non-TNBC controls. Serum starvation drastically up-regulated the phosphorylation of Bcl-2, and elevated autophagy level simultaneously. In addition, Autophagy inhibitors reduced the autophagy level in non-TNBC, while inhibiting the cell proliferation. These results suggested that autophagy might be involved in breast cancer, and pBcl-2 might regulate breast cancer through the autophagic pathway. Therefore, to further investigate the role of Bcl-2 and autophagy in TNBC, we would collect TNBC and non-TNBC cells as control, identify the difference on autophagy, mitochondrial function and cell proliferation between TNBC and non-TNBC cells through manipulating the expression of Bcl-2 or autophagy related genes. Together with existing therapeutic methods, this work would provide a potential option for TNBC clinical diagnosis and the targeted treatment.

三阴性乳腺癌至今无靶向药物，作为标准疗法的化疗既具毒副作用，且约1/3的患者产生抗性，因此解析三阴性乳腺癌的发病机理对靶向治疗具有一定的理论指导意义。Bcl-2、自噬及线粒体调控异常均与乳腺癌密切相关，但它们在三阴性乳腺癌中的调控作用及相互关系尚不清楚。我们初步发现：三阴性乳腺癌组织和细胞株中，Bcl-2的表达和自噬水平显著低于非三阴性组织和细胞。血清饥饿方法可显著上调三阴性乳腺癌细胞pBcl-2的表达，自噬也同时增高；自噬抑制剂降低了非三阴性乳腺癌细胞的自噬，同时抑制了细胞增殖。这些结果表明自噬很可能参与乳腺癌的调控，且pBcl-2可能通过自噬途径参与乳腺癌的调控。因此本项目拟以三阴性及非三阴性乳腺癌细胞为材料，通过调控Bcl-2及自噬相关基因，检测Bcl-2与自噬（线粒体自噬）、线粒体功能及细胞增殖的关系，以探求Bcl-2及自噬在三阴性乳腺癌中的作用机制，有望为其靶向治疗提供理论依据。

三阴性乳腺癌至今无靶向药物，且约1/3的患者对化疗产生抗性，因此解析三阴性乳腺癌的发病机理对靶向治疗具有一定的理论指导意义。Bcl-2、自噬及线粒体调控异常均与乳腺癌密切相关，但它们在三阴性乳腺癌中的调控作用及相互关系尚不清楚。我们的研究发现：三阴性和非三阴性乳腺癌细胞株中，Bcl-2的表达存在差异。内源性和外源性调高Bcl-2的表达可诱发自噬，促进细胞增殖；降低Bcl-2的表达可抑制自噬和细胞增殖。而且自噬会增强细胞对药物的敏感性。进一步的研究表明自噬主要受pBcl-2调控，Bcl-2的3个关键位点的磷酸化决定了它与Beclin1及BAX的动态结合与解离，从而控制了细胞进行自噬还是凋亡，从而决定细胞在不同时间和外界条件下生存还是死亡，Bcl-2的磷酸化决定细胞命运。为临床上以Bcl-2的磷酸化为靶点，控制癌细胞的治疗提供理论依据。