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  • Periodic Report Summary 1 - TNBCHEMIRNET (Enhancing chemotherapy response in triple negative breast cancer (TNBC) by modulating miRNA-target network and identifying biomarkers of response)

Periodic Report Summary 1 - TNBCHEMIRNET (Enhancing chemotherapy response in triple negative breast cancer (TNBC) by modulating miRNA-target network and identifying biomarkers of response)

Summary of objectives: In the project entitled as “Enhancing chemotherapy response in triple negative breast cancer (TNBC) by modulating miRNA-Target network and identifying biomarkers of response”, we hypothesized that:
1.miRNAs/their target networks might play key roles in resistance to chemotherapies and can be modulated to enhance the chemotherapy response in TNBCs;
2.miRNAs can be used as biomarkers to predict response of TNBC patients to chemotherapy.

To test these hypotheses, we proposed the following specific objectives:
1.To develop chemoresistant (doxorubicin-resistant) TNBC models of (i) human xenografts in athymic Nu/nu mice (ii) syngeneic transplants from genetically engineered mouse model of TNBC
2.To perform whole-genome miRNA/mRNA sequencing in chemo-sensitive versus chemoresistant tumors to identify miRNA/target networks involved in chemoresistance
3.To target miRNAs or their functional targeting networks to prevent/delay chemoresistance and to enhance chemoresponse
4.To test if miRNA/target expression can be used as biomarkers to predict chemoresponse in TNBC patients.

Work done: In line with above mentioned objectives, we started with developing chemoresistant TNBC model of human xenografts by injecting TNBC cells subcutaneously without incision in mammary fat pads of athymic Nu/nu mice. Tumor growth was monitored by measuring the tumor volume every 3 days. When the tumors reached 4-5 mm diameter (within 2-3 weeks), mice were treated intravenously (I.V) with doxorubicin (5 mg/kg) or vehicle weekly. Tumors in doxorubicin treated mice showed sensitivity towards treatment in the beginning, but gradually developed resistance over time. We collected different numbers of vehicle treated (control), doxorubicin sensitive and resistant tumors. Later, depending on net fold change in tumor volume, we selected 4 tumors per group (control, doxorubicin sensitive and resistant), and moved towards 2nd objective of the project where we performed whole-genome miRNA/mRNA sequencing for these tumors. Following the analysis, we uploaded miRNAs and mRNAs differentially expressed between doxorubicin sensitive and resistant tumors to Ingenuity Pathway Analysis (IPA), and performed miRNA target predictions. At the end of this analysis, we built a chemoresistance miRNA-mRNA network encompassing 26 miRNAs and 103 mRNAs (making 157 miRNA-mRNA nodes) differentially expressed between doxorubicin sensitive and resistant tumors. Lastly, using ChipBase online tool, we incorporated transcription factors regulating miRNAs in the network based on their differential expression between sensitive and resistant tumors.

Main results: So far, we have worked in line with our work plan. We successfully developed one of the chemoresistant TNBC model, and using miRNA- and RNA-sequencing data from this model and with the help of bioinformatics tools, we have developed miRNA-mRNA network regulating chemoresistance in TNBC. We have successfully achieved all the goals for the first time period with an exception that we developed just one of the chemoresistant TNBC model rather than two. In this regard, we have plans that we will develop second chemoresistant TNBC model during the second reporting period to use it as a validation model for the network we developed from the first chemoresistant TNBC model. We have also identified key pathways which might causally be involved in chemotherapy resistance in TNBC.

Expected Results: This project will provide important insights into the role of miRNAs in chemotherapy response in 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.

Socio-economic impact and societal implications: As response to chemotherapy strongly correlates with TNBC patients’ survival, increasing the pCR rate to chemotherapy is expected to significantly improve TNBC patient survival. If successful, this project has potential both (1) to stratify the patient subpopulations with higher likelihood of response to chemotherapy (2) to increase the survival of TNBC patients by enhancing the pCR rate to standard chemotherapy. Considering that around 15% of breast cancers diagnosed worldwide (totaling almost 200,000 new cases each year) is TNBC, choosing right patient population for chemotherapy and enhancing the pCR rate will both increase the survival of patients suffering from TNBC and save the tax-payers’ money in Europe and in the world. To the best of our knowledge, the role of miRNAs in chemo-response or -resistance of TNBC at network level has never been studied before. Another novelty of the proposed project is that identifying the targeting network (targetome) of the miRNAs playing potential role in chemoresistance of TNBCs may lead us to develop combinatorial therapies which can block several oncogenic pathways simultaneously. If there are chemical inhibitors or antibodies available for the identified targets, a rapid translation to clinics could be envisioned by initiating clinical trials combining chemotherapy with the identified combinatorial therapies. Furthermore, considering the rapid developments in miRNA biology, miRNA targeting approaches and miRNAs as biomarkers, the findings of proposed project can substantially contribute to both better understanding of the disease and better targeting/stratifying the TNBC patient populations.

The project website is ( open and up to date for further information.

Reported by

Bilkent Üniversitesi


Life Sciences
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