Congratulations to our CSI PhD students, Eve Wang Chao and Shreya Kar, from Dr Alan Prem Kumar’s group for winning awards at the 10th Global Breast Cancer Conference!

Hosted by the Korean Breast Cancer Society and supported by the Korean Breast Cancer Foundation, this conference took place in Jeju Island, South Korea, from 20-22 April 2017. The GBCC aims to increase global awareness of breast cancer, develop better knowledge of the disease and its medical treatments, and improve the quality of life of breast cancer patients.

Over 1000 participants from 30 countries attended the GBCC, making it a very rewarding and beneficial meeting. Researchers had the wide opportunity to share and discuss their research progress and gain fruitful insights. Eve was delighted to meet international clinicians and be offered the opportunity to broaden her knowledge about the advancements and challenges of breast cancer treatment in clinical settings. This has highly inspired her to better connect her research with clinical settings to truly benefit breast cancer patients in the future.

BACKGROUND: Statins, commonly used for the treatment of hypercholesterolemia, inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) of the mevalonate pathway. Simvastatin use was found to associate with a reduced risk of breast cancer recurrence. While the anti-tumor effects of statins were widely reported, few studies utilised  biomarkers to obtain consistent outcomes. In this study, we investigated the possibility of using DDX20, an oncogene recently uncovered by our group, as a surrogate marker for statin response in breast cancers.
METHODS: We first assessed correlation between mevalonate pathway genes and DDX20 expression in 1325 breast tumors, with HMGCR showing the highest positive correlation. Breast cancer cells were then treated with simvastatin and mevalonate pathway intermediates to assess the alteration in DDX20 expression. In the mouse model and clinical trials, simvastatin was administered and tissue samples were obtained for IHC staining of DDX20 and tumour markers.
RESULTS: Both in vitro and in vivo studies demonstrate that high triple negative breast cancer  (TNBC) with high DDX20 is more sensitive to simvastatin than breast cancer with low DDX20 level. Exposure of TNBC cells to statins decreases DDX20 expression in a mevalonate pathway-dependent manner via RhoA. Similar activity was observed in tumor biopsies in mice and breast cancer patients. As a recent study reported the mevalonate pathway regulates YAP via RhoA, we have uncovered an interplay between DDX20 and YAP-TEAD complex.
CONCLUSIONS: An implication of our findings is a combinatorial therapy using statins (to suppress DDX20) and a first-line agent “for the kill” of TNBC.

Role of PPAR? Activation in the Dynamics of Macrophage Polarization in Breast Cancer

BACKGROUND: Macrophages in the complex architecture of tumor microenvironment exhibit cellular plasticity and have various subtypes with distinct phe

notypic properties. Peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-activated transcription factor expressed in macrophages and has been shown to promote macrophages to alternatively activated M2 phenotype in metabolic diseases. Its role in macrophage polarization in breast cancer is not fully understood.
METHODS: CD206 and CD163(M2 markers) expression was evaluated in the breast cancer patient’s data extracted from Gene Expression Omnibus (GEO) and ArrayExpress. Percentage of CD206+ macrophages was evaluated using flow cytometry in the breast tumors from MMTV mice and the mammary fat pad of the control mice along with the gene expression of PPAR?. Macrophage education by murine breast cancer cells was assessed by ex vivo differentiation of bone-marrow derived macrophages(BMDMs) in the presence or absence of breast cancer cell conditioned media and also PPAR? agonist. Obtained macrophages were analyzed by flow cytometry, ELISA and mRNA expression.
RESULT: Clinically we found that CD163+ and CD206+ M2-macrophages were strongly associated with invasive-Claudin-low subtype. In the MMTV mouse model, CD206+ macrophages were higher in the breast tumors as compared to control mammary tissues. Interestingly, data from patients also revealed a strong positive correlation between expression of CD206, CD163 and PPAR?. Furthermore, the most metastatic cell line 4T1 and PPAR? agonists, skew macrophages toward the more immunosuppressive M2 subtype.
CONCLUSIONS: This study demonstrates that breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates positively with PPAR? expression. Further studies need to be done in order to explore the signaling mechanism involved in governing this dynamic process.