Journal Article

FAK activates AKT-mTOR signaling to promote the growth and progression of MMTV-Wnt1-driven basal-like mammary tumors

Yeo, Syn Kok, Paul, Ritama, Luo, Ming, Mo, Xueying, Lu, Jason, Guan, Jun-Lin

2020

Overview

Background Breast cancer is a heterogeneous disease. Hence, stratification of patients based on the subtype of breast cancer is key to its successful treatment. Among all the breast cancer subtypes, basal-like breast cancer is the most aggressive subtype with limited treatment options. Interestingly, we found focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase, is highly overexpressed and activated in basal-like breast cancer. Methods To understand the role of FAK in this subtype, we generated mice with conditional deletion of FAK and a knock-in mutation in its kinase domain in MMTV-Wnt1-driven basal-like mammary tumors. Tumor initiation, growth, and metastasis were characterized for these mice cohorts. Immunohistochemical and transcriptomic analysis of Wnt1-driven tumors were also performed to elucidate the mechanisms underlying FAK-dependent phenotypes. Pharmacological inhibition of FAK and mTOR in human basal-like breast cancer cell lines was also tested. Results We found that in the absence of FAK or its kinase function, growth and metastasis of the tumors were significantly suppressed. Furthermore, immunohistochemical analyses of cleaved caspase 3 revealed that loss of FAK results in increased tumor cell apoptosis. To further investigate the mechanism by which FAK regulates survival of the Wnt1-driven tumor cells, we prepared an isogenic pair of mammary tumor cells with and without FAK and found that FAK ablation increased their sensitivity to ER stress-induced cell death, as well as reduced tumor cell migration and tumor sphere formation. Comparative transcriptomic profiling of the pair of tumor cells and gene set enrichment analysis suggested mTOR pathway to be downregulated upon loss of FAK. Immunoblot analyses further confirmed that absence of FAK results in reduction of AKT and downstream mTOR pathways. We also found that inhibition of FAK and mTOR pathways both induces apoptosis, indicating the importance of these pathways in regulating cell survival. Conclusions In summary, our studies show that in a basal-like tumor model, FAK is required for survival of the tumor cells and can serve as a potential therapeutic target.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: AKT protein / Analysis / Animals / Apoptosis / Basal-like breast cancer / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer metastasis / Cancer Research / Cancer therapies / Carcinoma, Basal Cell - genetics / Carcinoma, Basal Cell - metabolism / Carcinoma, Basal Cell - pathology / Caspase-3 / Cell death / Cell growth / Cell migration / Cell Movement - physiology / Cell Proliferation - physiology / Cell survival / Cell Transformation, Neoplastic / Development and progression / Disease Models, Animal / Disease Progression / FAK / Female / Flow cytometry / Focal adhesion kinase / Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors / Focal Adhesion Protein-Tyrosine Kinases - genetics / Focal Adhesion Protein-Tyrosine Kinases - metabolism / Gene amplification / Gene deletion / Gene set enrichment analysis / Growth / Growth factors / Humans / Kinases / Ligands / Mammary gland / Mammary Neoplasms, Experimental - genetics / Mammary Neoplasms, Experimental - metabolism / Mammary Neoplasms, Experimental - pathology / Mammary Tumor Virus, Mouse - genetics / Metastases / Mice, Transgenic / mTOR / Oncology / Penicillin / Phenotypes / Phosphorylation / Protein-tyrosine kinase / Proteins / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Research Article / Signal Transduction / Software / Surgical Oncology / Therapeutic applications / TOR protein / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism / Tumor cell lines / Tumor cells / Tumor Cells, Cultured / Tumors / Tyrosine / WNT1 / Wnt1 Protein - genetics / Wnt1 Protein - metabolism / Wound healing