Cullin-5 deficiency orchestrates the tumor microenvironment to promote mammary tumor development through CREB1-CCL2 signaling
Si Chen, Fangyuan Shao, Jianming Zeng, Sen Guo, Lijian Wang, Heng Sun, Josh Haipeng Lei, Xueying Lyu, Shuai Gao, Qiang Chen, Kai Miao, Xiaoling Xu, Chu‐Xia Deng
Abstract
Breast cancer–associated gene 1 ( Brca1 ) deficiency induces the onset of breast cancer formation, accompanied with extensive genetic alterations. Here, we used both the sleeping beauty transposon mutagenesis system and CRISPR-Cas9–mediated genome-wide screening in mice to identify potential genetic alterations that act synergistically with Brca1 deficiency to promote tumorignesis. Both approaches identified Cullin-5 as a tumor suppressor, whose mutation enabled Brca1 -deficient cell survival and accelerated tumorigenesis by orchestrating tumor microenvironment. Cullin-5 suppresses cell growth through ubiquitylating and degrading adenosine 3′,5′-monophosphate–responsive element binding protein 1 (CREB1), especially under protein damage condition. Meanwhile, Cullin-5 deficiency activated CREB1-CCL2 signaling and resulted in the accumulation of monocytes and polymorphonuclear myeloid–derived suppressor cells, reduction of T cells that benefit tumor progression in both Brca1 -deficient cells and wild-type cells. Blocking CREB1 activity either through gene knockout or specific inhibitor treatment suppressed changes in the tumor microenvironment caused by Cullin-5 deficiency and blocked tumor progression.