Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Cancer Res. 2012 Jul 1;72(13):3119-24. doi: 10.1158/0008-5472.CAN-11-3891. Epub 2012 Jun 15.
The overexpression of MYC, which occurs in many tumors, dramatically disrupts the equilibrium between activation and repression of the oncogenic MYC/MYC-associated protein X (MAX)/MAX dimerization protein 1 (MXD1) network, favoring MYC-MAX complexes and thereby impairing differentiation and promoting cell growth. Although for some time it has appeared that MAX is necessary for both the activation and repression of the axis, recent evidence shows that MYC retains considerable biologic function in the absence of MAX. The presence of germline MAX mutations in patients with hereditary pheochromocytoma supports the predominant role of MAX as a negative regulator of the network and suggests that MYC deregulation plays a role in hereditary cancer predisposition. This finding also confirms the importance of impairment of the MYC/MAX/MXD1 axis in the development of aggressive neural tumors, because MYCN overexpression is an established genetic hallmark of malign neuroblastoma, and it is likely that MXI1 plays a relevant role in the development of medulloblastoma and glioblastoma. Finally, the likely malignant behavior of tumors with mutations in MAX points to MYC as a candidate therapeutic target in the treatment of metastatic pheochromocytoma.
MYC 的过表达发生在许多肿瘤中，它会极大地破坏致癌 MYC/MYC 相关蛋白 X（MAX）/MAX 二聚化蛋白 1（MXD1）网络的激活和抑制之间的平衡，有利于 MYC-MAX 复合物的形成，从而损害分化并促进细胞生长。尽管一段时间以来，MAX 似乎对轴的激活和抑制都是必需的，但最近的证据表明，在没有 MAX 的情况下，MYC 仍然具有相当大的生物学功能。遗传性嗜铬细胞瘤患者中存在种系 MAX 突变支持了 MAX 作为该网络负调节剂的主要作用，并表明 MYC 失调在遗传性癌症易感性中发挥作用。这一发现也证实了 MYC/MAX/MXD1 轴的损伤在侵袭性神经肿瘤发展中的重要性，因为 MYCN 的过表达是恶性神经母细胞瘤的既定遗传标志，而且 MXI1 可能在髓母细胞瘤和胶质母细胞瘤的发展中发挥相关作用。最后，MAX 突变的肿瘤可能具有恶性行为，这表明 MYC 是治疗转移性嗜铬细胞瘤的候选治疗靶点。
