MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.

Abstract

The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Inactivating mutations in <i>MAX</i> are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma, and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting <i>Max</i> across multiple mouse neuroendocrine tissues, we find that <i>Max</i> inactivation alone produces pituitary adenomas, while <i>Max</i> inactivation cooperates with <i>Rb1</i>/<i>Trp53</i> loss to accelerate medullary thyroid C cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a marked shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival, and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.