Csn-B,a Small Molecular Compound,inhibits The Development Of Breast Cancer By Targeting Nur77

Breast cancer is the most diagnosed cancer and the leading cause of cancer mortality among women worldwide,affecting about 2.1 million women every year.Therapeutic strategies based on cancer subtype have improved the clinical outcome of patients with breast cancer in recent decades,but a vast majority of patients diagnosed with advanced breast cancer are confronted with treatment resistance because of the tumor heterogeneity.A better understanding of the mechanisms underlying malignant progression of breast cancer and identifying new therapeutic targets and drugs are of high urgency.Our previous study showed that in breast cancer cells Nur77 was a key player in repressing uptake of exogenous fatty acids through transcriptionally repressing CD36 and FABP4 expressions,leading to the inhibition of breast cancer development.Nevertheless,this role of Nur77 was nullified during breast cancer progression due to highly expressed nuclear receptor PPARγ that interacted with Nur77 to recruit ubiquitin ligase Trim13 to target Nur77 for degradation.In the present study,we identified a small molecule compound Csn-B that can inhibit the development of breast cancer by targeting Nur77.Csn-B could inhibit cell proliferation in MCF-7 cells and the primary tumor cells from PyMT-WT but not PyMT-KO mice.And the physiological potential of Csn-B was also investigated.CsnB treatment sufficiently retarded tumor initiation,caused a significant delay in tumor progression in MMTV-PyMT spontaneous mouse model and MPA-DMBA induced mouse model.And immunohistochemical analysis revealed that Csn-B treatment significantly enhanced Nur77 protein levels in both mouse models.Mechanistically,Csn-B inhibited breast cancer by disrupting the association between Nur77 and PPARγ.Enhancing the Nur77-Nur77 homodimeric interaction by Csn-B impeded the formation of the Nur77-PPARγ heterodimer.And the interference on the PPARγ-Nur77 interaction could improve Nur77 stability to enhance transcriptional inhibition of fatty acid uptake related genes CD36 and FABP4,thereby inhibiting fatty acid uptake.Finally,we found that Csn-B lost the capacity to facilitate the formation of dimeric Nur77D481A/Q571A/P572W,and a reintroduction of Nur77D481A/Q571A/R572W did not compensate for the role of Nur77 in Csn-B induced inhibition of fatty acid uptake in Nur77 knocking down MCF-7 cells.This study identifies Csn-B as an effective therapeutic lead compound for breast cancer,providing a new idea for the treatment of breast cancer.