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

Abstract

Breast cancer-associated gene 1 (<i>Brca1</i>) 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 <i>Brca1</i> deficiency to promote tumorignesis. Both approaches identified Cullin-5 as a tumor suppressor, whose mutation enabled <i>Brca1</i>-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 <i>Brca1</i>-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.