维生素D在乳腺癌防治中的作用及其机制研究

Breast cancer is a malignant tumor with high incidence among women, but the pathogenesis is not yet clear. Several studies have found that vitamin D can reduce the incidence of breast cancer and improve the prognosis of breast cancer patients. Applicant's preliminary studies found that vitamin D can cause high expression of CYP24A1, a key vitamin D catabolic enzyme in breast cancer cells, resulting in a negative feedback regulation to reduce the function of vitamin D locally; The key catabolic enzyme CYP24A1 promotes breast tissue growth and development. Accordingly, applicant hypothesized that CYP24A1 plays a critical role in the prevention and treatment of breast cancer. To verify this hypothesis, this project intends to adopt a variety of molecular biological techniques and animal experiments to fully assess the differential expression of CYP24A1 between breast cancer and adjacent normal tissues, to determine the role of combining CYP24A1 inhibitor with vitamin D in the treatment of breast cancer, and to investigate the molecular mechanism of CYP24A1 in the growth, invasion and metastasis of breast cancer. Applicants have been engaged in breast cancer related research for a long time and have excellent research foundation. The project is innovative and has pivotal theoretical significance and potential transformation value.

乳腺癌作为在女性中一种发病率高的恶性肿瘤，其发病机制尚未明确。多项研究发现维生素D可以降低乳腺癌发生和改善乳腺癌预后。申请者前期研究发现，维生素D可引起乳腺癌细胞代谢关键酶CYP24A1基因表达水平显著升高，反馈性降低维生素D在局部的作用；代谢关键酶CYP24A1促进乳腺组织生长发育。据此，申请者提出假说，维生素D代谢关键酶CYP24A1作为新的靶点在乳腺癌的预防和治疗中发挥重要作用。为验证这一假说，本课题拟利用多种分子生物学技术和动物实验全面评估维生素D代谢关键酶CYP24A1在各种亚型乳腺癌和癌旁组织的差异性表达，确定维生素D代谢关键酶CYP24A1抑制剂联合维生素D在乳腺癌治疗中的作用，探讨维生素D代谢关键酶CYP24A1及关键信号通路参与乳腺癌生长、侵袭及转移的分子机制。申请者长期从事乳腺癌相关研究，工作基础良好；课题创新性明显，具有重要理论意义与潜在应用转化价值。

维生素D是是人体必需的维生素，具有抗肿瘤活性，但其具体的抗癌机制尚不明确。首先评估了维生素D在预防乳腺癌中的作用，研究发现口服维生素D对于预防乳腺癌的发生发展的作用非常有限，容易产生耐药；其次揭示维生素D关键代谢酶CYP24A1是导致维生素D体内失活的关键酶，体外细胞实验和乳腺癌组织体外培养实验也证实肿瘤细胞在接触大剂量的维生素D或其代谢活性产物，其关键代谢酶CYP24A1的表达量会明显升高，导致维生素D活性产物失活，限制其抗癌活性；进一步通过转基因小鼠模型敲除Cyp24a1代谢酶，乳腺导管上皮的增殖受到明显的抑制，Cyp24a1的敲除对维生素D抑制乳腺导管上皮细胞的增殖起到明显的增敏作用。本项目的研究结果为后续高选择性的CYP24A1代谢酶抑制剂的研究和开发提供作用的理论依据和研究方向。