IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Cells

J.Silvio Gutkind¹  Francesca Cirillo²  Rosamaria Lappano²  Marianna Talia²  Domenica Scordamaglia²  Marcello Maggiolini²  DamianoCosimo Rigiracciolo²  Nijiro Nohata³ 

[1] Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA;Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;MSD K.K., Tokyo 102-8667, Japan;

关键词: TNBC;    IGF-1;    IGF-1R;    FAK;    YAP;    OSI-906;   

DOI  :  10.3390/cells9041010

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown