Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.
Highlights
Breast cancer is the most frequently diagnosed malignant disease among women worldwide and is the main cause of cancer-related deaths [1]
By mining the RNA-sequencing data of the Breast Cancer Cohort of the vast public databases Cancer Genome Atlas (TCGA) (The Cancer Genome Atlas: https://cancergenome.nih-gov/) and microarray data of METABRIC, we evaluated the Kaplan-Meier survival rates of patients grouped according to high expression levels of insulin-like growth factor-1 (IGF-1) or insulin-like growth factor 1 receptor (IGF-1R) and low expression levels of IGF-1 and IGF-1R
Our analysis revealed that a high expression of IGF-1 or IGF-1R does not affect the Overall Survival (OS) or Disease-Free Survival (DFS) rates in patients with estrogen receptor- (ER)/progesterone receptor (PR)-positive and human epidermal growth receptor 2 (HER2)-negative breast cancer subtype, but it associates with a reduced DFS rate in triple-negative breast cancer (TNBC) patients
Summary
Breast cancer is the most frequently diagnosed malignant disease among women worldwide and is the main cause of cancer-related deaths [1]. Meaningful progress has been recently made in the early detection and treatment of breast cancer. A wide number of patients may relapse as a consequence of distant metastasis, in particular those affected by the highly malignant triple-negative breast cancer (TNBC) subtype [2]. Of all diagnosed breast carcinomas, is characterized by aggressive biological features leading to a poor clinical outcome [3,4]. Considering the worst prognosis and the lack of targeted treatments of TNBC, major efforts are required for setting novel therapeutic strategies [4]. The insulin-like growth factor-1 (IGF-1) binding to the insulin-like growth factor receptor-type
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
