Congratulations to Dr Alan Prem Kumar, CSI Principal Associate who clinched the Outstanding Oral Presentation Award at the recent Global Breast Cancer Conference (GBCC), hosted by the Korean Breast Cancer Society and supported by the Korean Breast Cancer Foundation, which was held on 5-7 April 2018 at Incheon, South Korea.
Marked as one of the biggest breast cancer conferences in Asia, the GBCC 2018 saw more than 1,000 participants in its recent assembly. This conference aims to seek integrative collaboration with medical professionals and experts across the globe to advance the sphere of breast cancer and provide effective treatment for breast cancer patients.
We also extend our heartiest compliments to Shreya Kar, PhD student from Dr Alan Prem Kumar’s group, for winning the Best Outstanding Poster Presentation during the conference. It was indeed a rewarding experience for Shreya as she had the opportunity to share and discuss research progress as well as to gain great clinical insights during this conference.
Dead-box RNA Helicase DP103 Enhances Yap Sumoylation for Yap-tead Dependence and Statin Sensitivity in Triple Negative Breast Cancer
BACKGROUND: Simvastatin, a lipophilic statin used for lowering cholesterol, inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the key enzyme of the mevalonate pathway. Studies have shown that cancer cells express deregulated level of HMGCR and statins exert anti-tumoral activities.
METHODS: We first assessed correlation between mevalonate pathway genes and DDX20 (DP103, Gemin-3) in 1325 breast cancer patients and observed a positive correlation between DDX20 and the mevalonate pathway genes. Having this data, we then proceeded to explore the effect of statins on DDX20 expression. We used various in vitro cell lines and in vivo statin clinical trial patients’ specimens, mouse xenograft, mouse intravenous tail injection and Drosophila (wild-type vs Gemin-3 knockdown vs Gemin-3 overexpression flies) models.
RESULTS: We show exposure to statin decreases the expression of DDX20. Through a series of add-back experiments, we show that the decrease in DDX20 expression by statins is via the mevalonate pathway and downstream of RhoA. In clinical specimens, we observed breast cancer patients with high baseline DDX20 positively correlates with high baseline YAP-TEAD expression. Having known that SUMOylation of YAP maintains its activity and that DDX20 is a critical enhancer of the SUMOlyation machinery, we showed through a series of experiments that a physical interaction between DDX20 and YAP is crucial for maintaining SUMOylation of YAP; thereby decreasing its ubiquitination and degradation.
CONCLUSION: Interestingly, we also identified for the first time that DDX20 is a direct target of YAP-TEAD complex and that maintenance of DDX20 expression is needed as a positive feedback forming an Achilles heel for sustained YAP-TEAD activity.
Shreya Kar – Best Poster Award
”Annex” in A1 to the Breast Tumour Microenvironment by Aiding in Macrophage Polarisation
BACKGROUND: Tumor-associated macrophages(TAMs)choreograph various aspects of the tumor microenvironment.Macrophages exhibit cellular plasticity and can be polarized to M1/M2 subtypes in presence of different microenvironment “signals”. Annexin A1(ANXA1),an anti-inflammatory protein is highly expressed in metastatic breast cancer.
METHODS: The association between TAMs and breast cancer in the patients was assessed.Percentage of M1/M2 macrophages was evaluated in the breast tumors from MMTV mice. Macrophage education by breast cancer was assessed by ex vivo differentiation of bone-marrow derived macrophages(BMDMs) in the presence or absence of breast cancer conditioned media by flow cytometry,ELISA, and mRNA expression.
RESULT: Clinically,we found that M2 TAMs were highly enriched in Claudin-low breast cancer subtype and was strongly associated with ANXA1 gene expression.In the MMTV mouse model,M2 TAMs were higher in the breast tumors compared to the mammary tissues along with higher expression of ANXA1.Additionally, wild type BMDMs were skewed to a more M2 TAM-like phenotype upon co-culture with breast cancer cells,with enhanced migratory and invasive properties and phagocytic potential,which was reduced in the ANXAI-knockout BMDMs.Breast tumors isolated from the 4T1-orthotopic mouse model showed higher percentage of M2 TAMs in the wild type as compared to the ANXA1 KO mice.
CONCLUSION: This study demonstrates a novel role of ANXA1 in regulating the dynamic aspect of macrophage polarization in breast tumor microenvironment.RNA sequencing is underway to explore the unique signature molecules and the signaling mechanism involved in governing this entropic process.Secretome analysis (underway) of breast cancer conditioned media for the evaluation of various secreted proteins will also unveil important information pertaining to this dynamic process.