Congratulations to CSI Graduate Students Eve Wang Chao and Shreya Kar who recently won awards at the New Zealand Breast Cancer Symposium (NZBCS)! Eve and Shreya, who are from Dr Alan Prem Kumar’s group, attended the NZBCS which was held from 12-14 November in Auckland.

NZBCS-2017 is the New Zealand’s first breast cancer symposium with a vision of “United for a Cure through Research”; helping women with breast cancer live longer. It aims to promote basic and clinical research on breast cancer, stimulate domestic and international collaborations, and expedite the translation of laboratory discoveries into clinical applications, for improved treatment of those with breast cancer.

Eve and Shreya presented their research work at the symposium and were awarded the first and second prize respectively for ‘Emerging Scientists Oral Presentation’.

In addition to their achievements, they also took home with them a deeper knowledge about breast cancer research from the global data, and learnt about the disease state of breast cancer in New Zealand, which will enable them to make more inroads into local research on breast cancer, which is the No.1 cancer affecting women in Singapore.

 

 

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Abstract (Eve Wang)

Interplay between Mevalonate and Hippo Pathways Regulates DDX20 Transcription via YAP-TEAD Complex in invasive Breast Cancers

Statins, the widely used cholesterol-lowering drugs, have been reported to exhibit pleiotropic functions, particularly anti-tumor activity. Despite notable evidence for statins as anti-tumor agents, clinical trials have demonstrated controversial results in breast cancers. A likely reason is the lack of biomarkers to identify responsive patients. In this study, we investigated using DDX20, an oncogene recently uncovered by our group, as a surrogate marker for statin response in breast cancers. We first assessed correlation between mevalonate pathway genes and DDX20 in 1325 breast tumors and a positive correlation between DDX20 and the mevalonate pathway genes was observed. Subsequently, we found that statin was able to significantly decrease DDX20 expression in MDA-MB-231 cells and in a breast cancer xenograft mouse model. To examine if statin-induced downregulation of DDX20 is translated to patients, we obtained tissues from a clinical trial where breast cancer patients were administered with simvastatin. Taken together, the in vitro, in vivo and clinical data all confirmed that simvastatin decreased DDX20 expression. Moreover, we also revealed that DDX20 is regulated by statin-GGPP-RhoA axis. Interestingly, a recent study reported that YAP, the downstream effector of the Hippo pathway, is also regulated via GGPP-RhoA axis and YAP was shown to interact with DDX17, which belongs to the DEAD box family like DDX20. Therefore, it prompted us to find if there is an interplay between DDX20 and YAP. Our results indicated a direct interaction between DDX20 and YAP. Furthermore, we observed an increased level of DDX20 upon YAP overexpression and patients with higher YAP expression showed higher expression of DDX20, suggesting DDX20 could be a novel YAP target gene. Overall, our study identified a new target of the Hippo pathway, which could be inhibited by statin. Potential application is a combinatorial therapeutic using statins to suppress DDX20 and a first-line agent to treat invasive breast cancers.

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Abstract (Shreya Kar)

Crosstalk between PPAR? and Annexin A1 in Tumor-Associated Macrophages in Breast Cancer

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”. Peroxisome proliferator-activated receptor gamma(PPAR?) is a ligand-activated transcription factor expressed in macrophages, which has been shown to polarize macrophages towards the activated M2 phenotype in metabolic diseases. Annexin A1(ANXA1), an anti-inflammatory protein is highly expressed in metastatic breast cancer. TAMs expression was evaluated in the breast cancer patient samples. Percentage of TAMs was evaluated using flow cytometry in the breast tumors from MMTV mice along with the gene expression of PPAR? and ANXA1.Macrophage education by breast cancer cells was assessed by ex vivo differentiation of bone marrow derived macrophages(BMDMs) by flow cytometry, western blotting and mRNA expression.Clinically, we found that M2 TAMs were highly enriched in Claudin-low breast cancer subtype and was strongly associated with PPAR? and ANXA1 expression. In the MMTV mouse model, TAMs were higher in the breast tumors compared to the normal mammary tissues. Additionally, the BMDMs were skewed to a more M2 TAM-like phenotype upon co-culture with breast cancer cells as well as upon treatment with PPAR? agonist. Interestingly, upon treatment with the breast cancer conditioned media, expression of PPAR? along with its downstream targets was reduced in ANXAI-knockout BMDMs as compared to its wild type counterparts, suggesting a role of ANXA1 in regulating PPAR? activation.This study demonstrates a novel role ANXA1 in regulating expression of PPAR? in the TAMs of breast tumor microenvironment. Further studies are underway to explore the signaling mechanism involved in governing this dynamic process.