SUPPORT


Enhancing chemotherapy response in triple negative breast cancer by modulating miRNA-target network and identifying biomarkers of response

  • European Union Marie Curie Actions Career Integration Grant (MC-CIG10-631149-TNBChemiRNet), 2014-2018
  • PI: ÖZGÜR ŞAHİN
  • Total €100,000 for four years.
  • This project will provide important insights into the role of miRNAs in chemotherapy response in triple negative breast cancer (TNBC) patients. Proposed unbiased genome-wide profiling studies will identify miRNAs and their targeting networks which will be used to enhance response to chemotherapy, and our findings might be applicable to other cancer types, too. The biomarker analysis studies of patient specimen will provide important data that can potentially be used to stratify chemoresponsive versus non-responsive TNBC patients. Finally, our findings will provide crucial pre-clinical data to support a future clinical trial of chemotherapy in combination with miRNA or protein targeting therapies in TNBC patients.

 

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and therapies are primarily limited to conventional chemotherapy. TNBC patients who respond to neo-adjuvant chemotherapy with a pathological complete response (pCR) have excellent 5-year survival (up to 94%). However, this represents the minority of TNBC patients (25-40%). The remaining patients have less than 60% 5-year survival due to aggressive relapse. Therefore, increasing the pCR rate of chemotherapy in TNBC holds great promise for improving survival. Furthermore, it is important to identify biomarkers to predict/stratify TNBC patients with higher probability of response to chemotherapy. Recently, microRNAs (miRNAs), which are 20-22 nucleotide small RNAs, emerged as master regulators of several oncogenic processes including therapy resistance and have great potential to be used as therapeutics due to their ability to repress several oncogenic proteins simultaneously. Moreover, miRNAs have also been shown to be promising biomarkers for diagnosis, prognosis and therapy response in cancer. Herein I propose to study the potential for modulation of miRNAs/their target networks to enhance the response to chemotherapy and to identify biomarker of chemotherapy response in TNBC. In this line, I will develop in vivo chemoresistant models using both xenografts and tumor transplants from an established TNBC mouse model. Combining whole genome miRNA/mRNA sequencing, bioinformatics and network biology, miRNAs/their target network involved in chemoresistance will be identified, and targeted to enhance the chemoresponse of TNBC models. Finally, the biomarker potential of identified miRNAs/targets in TNBC patient tumors will be tested with inter-(national) collaborations from two different countries. Overall, this interdisciplinary study will provide pre-clinical data to enhance chemotherapy response in TNBC and identify biomarkers stratifying patients with higher response rate to chemotherapy.

 

Disseminations

  1. Manuscripts

“The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer” – Umar Raza, Özge Saatci, Stefan Uhlmann, Suhail Akhtar Ansari, Erol Eyüpoğlu, Emre Yurdusev, Merve Mutlu, Pelin Gülizar Ersan, Mustafa Kadri Altundağ, Jitao David Zhang, Hayriye Tatlı Doğan, Gülnur Güler and Özgür Şahin*. DOI: 10.18632/oncotarget.10489

* denotes corresponding author

  1. Invited talks

“Meme kanserinde ilaç direnç mekanizmaları ve metastaz”: Özgür Şahin – Hacettepe University, Ankara, 28th April, 2016.

“Systems biology of drug resistance and metastasis in breast cancer” Özgür Şahin – Middle East Technical University, Ankara, 27th April, 2016.

“Systems biology of drug resistance and metastasis in breast cancer”: Özgür Şahin – Boğaziçi University, Istanbul, 19th February, 2016.

“Meme kanserinde direnç mekanizmaları ve metastaz”: Özgür Şahin – Faculty of Medicine, Ankara University, Ankara, 25th November, 2015.

“Systems biology of drug resistance and metastasis” Özgür Şahin – EMBO YIP meeting, Barcelona, 13th-15th May, 2015.

“Identification of molecular switches regulating therapy resistance and metastasis in breast cancer”: Özgür Şahin – University of Erlangen, Erlangen, 27th January, 2015.

  1. Talks

“miR-644a inhibits both cell survival and EMT mediating drug resistance in breast cancer”: Umar Raza – 4th international Congress of the Molecular Biology Association of Turkey, Middle East Technical University, Ankara, 27th-29th November, 2015.

“miR-644: A novel tumor suppressor miRNA coregulating cell survival, chemo-response and EMT in breast cancer”: Umar Raza – Bilkent-Singapore Joint Workshop, Bilkent University, Ankara, 25th-26th May, 2015.

“miR-644: A novel tumor suppressor miRNA coregulating cell survival, chemo-response and EMT in breast cancer”: Umar Raza – Winter retreat organized by Molecular Biology Association of Turkey, Bilkent University, Ankara, 16th-17th January, 2015.

  1. Poster presentations

“A novel tumor suppressor miRNA co-regulating EMT and p53-independent cell survival in breast cancer”: Özgür Şahin – AACR Annual Meeting, 18th-22th April, 2015.

“miR-644: A novel tumor suppressor miRNA co-regulating EMT and cell survival in breast cancer”: Umar Raza – 3rd international Congress of the Molecular Biology Association of Turkey, Izmir Institute of Technology, Izmir, 10th-12th September, 2014.