Cullin-5 deficiency orchestrates the tumor microenvironment to promote mammary tumor development through CREB1-CCL2 signaling.

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.
Mesh Terms:
Animals, Cullin Proteins, Cyclic AMP Response Element-Binding Protein, Genes, Tumor Suppressor, Mammary Neoplasms, Animal, Mice, Signal Transduction, Tumor Microenvironment
Sci Adv
Date: Jan. 20, 2023
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