Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer

Assidicky, Ridho
Tokat, Unal Metin
Tarman, Ibrahim Oguzhan
Saatci, Ozge
Ersan, Pelin Gulizar
Raza, Umar
Ogul, Hasan
Riazalhosseini, Yasser
Can, Tolga
Sahin, Ozgur
Purpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes. Methods Here, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings. Results We identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients. Conclusion FN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.


Nuclear Deformability of Breast Cells Analyzed from Patients with Malignant and Benign Breast Diseases
Antmen, Ezgi; Ermiş Şen, Menekşe; Kuren, Ozgur; Beksac, Kemal; Irkkan, Cigdem; HASIRCI, Vasıf Nejat (2023-03-13)
Breast cancer is a heterogeneous and dynamic disease, in which cancer cells are highly responsive to alterations in the microenvironment. Today, conventional methods of detecting cancer give a rather static image of the condition of the disease, so dynamic properties such as invasiveness and metastasis are difficult to capture. In this study, conventional molecular-level evaluations of the patients with breast adenocarcinoma were combined with in vitro methods on micropatterned poly(methyl methacrylate) (PM...
Preparation and characterization of poly(d,l-lactide-co-glycolide) microspheres for controlled release of anticancer drugs
Eyövge, Gökçen; Gündüz, Ufuk; Department of Biotechnology (2005)
Breast cancer is the most frequent type of cancer seen in woman. Chemotherapy is one of the most important treatments for breast cancer. However, systemic toxicity, drug resistance and unstable kinetics of the drug in the blood are serious problems of chemotherapy. The use of biodegradable polymers for controlled release of anticancer drugs has gained popularity in recent years. Controlled release of anticancer drugs from polymeric carriers has some advantages such as improvement in the efficiency of treatm...
Novel ferrocenyl pyrazoles inhibit breast cancer cell viability via induction of apoptosis and inhibition of PI3K/Akt and ERK1/2 signaling
Atmaca, Harika; Ozkan, Ayse Nur; Zora, Metin (2017-02-01)
Despite the advances in early detection and targeted therapies, chemotherapy is still of vital importance in breast cancer treatment. However, development of drug resistance and serious side effects limits their usage. Thus, there is an urgent need for safer and more effective agents against breast cancer. We have previously described the synthesis of a number of pyrazole derivatives, and in the current study, we have investigated the effects of two different ferrocenyl pyrazole (FP) derivates, 5-ferrocenyl...
Multidrug resistance in logally advanced breast cancer
Atalay, Mustafa Can; Gündüz, Ufuk; Department of Biotechnology (2004)
Breast cancer is the most frequently detected cancer among women. Early diagnosis leads to long term survival when the patients are treated with surgery, radiotherapy, chemotherapy, and hormone therapy. Unfortunately, advanced disease could still be encountered in some patients resulting in a poorer prognosis. The primary treatment modality is chemotherapy for this group of patients. Drug resistance is a serious problem resulting in the use of different drugs during chemotherapy and knowing the possibility ...
Detection of Possible Significant Metabolites by Comparison of Metabolic Simulation Profiles of Healthy and Breast Cancer Tissues
Akkuzu Özyeşer, Selin; Bülbül, Abdullah Alper; Başaran, Gül; Sezerman, Osman Uğur (Orta Doğu Teknik Üniversitesi Enformatik Enstitüsü; 2022-10)
Breast cancer is the most frequent malignancy in women worldwide and is curable in ~70–80% of patients with early- stage, non- metastatic disease. In Breast cancer there are pathways related to Luminal A breast cancer, Luminal B breast cancer, HER2 positive breast cancer, Basal like/Triple negative breast cancer. The crucial signal transduction pathways in a breast cancerous cell includes pathways like PKB (protein kinase B), MAPK (mitogen-activated protein kinase), MTOR (mammalian target of rapamycin), Fas...
Citation Formats
R. Assidicky et al., “Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer,” BREAST CANCER RESEARCH AND TREATMENT, pp. 0–0, 2022, Accessed: 00, 2022. [Online]. Available: