Functional characterization of long non-coding RNA (lncRNA) and microRNA (miRNA) transcriptional landscape predictive of response to neoadjuvant chemotherapy in triple negative breast cancer

Breast cancer (BC) is the second most common cancer type around the world comprising approximately 11.6% of all new cancer cases and 6.6% of all cancer-related death up to 2018. Among females, BC is the most frequently diagnosed and the leading cause of cancer mortality. GLOBOCAN 2018 reported region-specific incidence and age-standardized mortality rate for BC in Western Asia (incidence: 45.3/100,000, mortality: 13.6/100,000) and Eastern Asia (incidence: 39.2/100,000, mortality: 8.6/100,000)[1]. The age-standardized incidence rate is growing in many countries, particularly in the Arab countries where the reported BC incidence ranges from 9·5–50 cases per 100,000 women per year{Chouchane, 2013 #2}. In the gulf region, the incidence of BC in Bahrain, United Arab Emirates, Saudi Arabia, Qatar, and Kuwait were 53.4, 22.8, 17.5, 48.2, and 46.6 cases per 100,000 women, respectively. Although the incidence of BC in this geographic region is lower than those reported in Europe and USA, the incidence of BC in Arab countries are on the rise [2]. Interestingly, patients diagnosed with BC in the Arab world are approximately a decade younger and they are oftentimes presented with larger and more advanced stage tumors{Chouchane, 2013 #2}. There are numerous risk factors for breast cancer, including age, family history, obesity and exposure to hormones and therapeutic radiation. [3] Models used to estimate breast cancer risk vary depending on population characteristics; however, with the exception of hormone prophylaxis, such models are not suitable for individual patient management. The two most common types of breast cancer are ductal and lobular carcinoma. An important issue for treatment is selecting the right therapeutic modality, which is largely dependent on disease subtype. Breast cancer is currently molecularly classified based on expression of sex hormone receptors and human epidermal growth factor receptor (HER)2, which can determine diagnostic approach and treatment choice. However, other methods of classification that are based on global gene expression are gaining momentum.[4] Molecular data – for instance, from oncotype DX breast cancer assays in lymph node-negative breast cancer – have increased our understanding of the mechanisms of chemotherapy and hormone resistance, such as the role of mutations in estrogen receptor (ER)1 in resistance to endocrine therapy. [5] Triple-negative breast cancer (TNBC) represents 15% to 20% of invasive breast cancers and is characterized by the lack of expression of estrogen and progesterone receptors and lack of amplification of HER2. TNBC patients do not benefit from endocrine therapy; therefore, surgery and chemotherapy is the main treatment modality. Cumulative evidence suggested added benefit for neoadjuvant chemotherapy (NAC) in a subset of triple negative breast cancer (TNBC) patients, therefore identifying the molecular signature predictive of the response of TNBC patients to NAC treatment could offer more personalized treatment choices for TNBC patients. Long non-coding RNAs and microRNAs has emerged as key players in cancer development, progression, and therapy failure. However, the role of this class of epigenetic regulators in mediating response to NAC in TNBC patients is beginning to unfold. The aim of the current study is reveal the lncRNA and miRNA transcriptional landscape TNBC patients and to devise a molecular signature predicative of the response of TNBC patients to neoadjuvant chemotherapy and to functionally characterize the role of the identified candidacies in mediating chemotherapy resistance. In this study, we will utilize our expertise in the field of miRNA and lncRNA and translational research and state-of-the-art facilities available at Qatar Biomedical Research Institute (QBRI) as well as internal collaboration with Dr Hirohito Yamaguchi with his expertise in mechanisms of chemotherapy resistance as well as international collaboration with Dr. Rory Johnson at Bern university in Switzerland, who is a world-renowned scientist in the non-coding RNA field. Additionally, this project will involve collaboration with king Hussain Cancer Center (KHCC), a leading cancer care center in the MENA region to achieve the goals of the study. At the end of this study, we expect to identify a set of lncRNAs and miRNAs that can predict the response of TNBC patients to neoadjuvant chemotherapy. The identified genetic signature can be used clinically to stratify the patients and personalized their treatment based on this genetic signature. Additionally, such discovery have the potential to be commercialized as novel genetic test for TNBC patients.

Hamad Bin Khalifa University (HBKU)