Cullin-5 deficiency orchestrates the tumor microenvironment to promote mammary tumor development through CREB1-CCL2 signaling.
Si ChenFangyuan ShaoJianming ZengSen GuoLijian WangHeng SunJosh Haipeng LeiXueying LyuShuai GaoQiang ChenKai MiaoXiaoling XuChu-Xia DengPublished in: Science advances (2023)
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.
Keyphrases
- genome wide
- induced apoptosis
- wild type
- crispr cas
- cell cycle arrest
- copy number
- binding protein
- replacement therapy
- dna methylation
- signaling pathway
- poor prognosis
- genome editing
- endoplasmic reticulum stress
- cell death
- gene expression
- type diabetes
- metabolic syndrome
- adipose tissue
- breast cancer risk
- drug delivery
- long non coding rna
- skeletal muscle
- immune response
- high fat diet induced
- genome wide analysis