Abstract
Triple negative breast cancer (TNBC) is a highly metastatic disease that currently lacks effective prevention and treatment strategies. The insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) signaling pathways function in numerous developmental processes, and alterations in both are linked with a number of common pathological diseases. Overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. The present study investigated the interrelationship between IGF1R and FAK signaling in regulating the malignant properties of TNBC cells. Using small hairpin RNA (shRNA)-mediated IGF1R silencing methods, we showed that IGF1R is essential for sustaining mesenchymal morphologies of TNBC cells and modulates the expression of EMT-related markers. We further showed that IGF1R overexpression promotes migratory and invasive behaviors of TNBC cell lines. Most importantly, IGF1R-driven migration and invasion is predominantly mediated by FAK activation and can be suppressed using pharmacological inhibitors of FAK. Our findings in TNBC cells demonstrate a novel role of the IGF1R/FAK signaling pathway in regulating critical processes involved in the metastatic cascade. These results may improve the current understanding of the basic molecular mechanisms of TNBC metastasis and provide a strong rationale for co-targeting of IGF1R and FAK as therapy for mesenchymal TNBCs.
Highlights
Triple-negative breast cancers (TNBCs) are distinguished by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression and constitutes up to 20% of all breast cancers cases
Immunoblotting analysis showed that the expression level of insulin-like growth factor 1 receptor (IGF1R) in MDA-MB-231/IGF1R-KD and BT549/ IGF1R-KD cells was reduced compared to empty vector (EV) control cells (Figure 1B), suggesting that lentivirus infection was highly efficient at inhibiting IGF1R expression
Our present study identifies a novel role for IGF1R signaling in the regulation of epithelial to mesenchymal transition (EMT) and provides new insight into the downstream processes regulated by IGF1R in TNBC cells
Summary
Triple-negative breast cancers (TNBCs) are distinguished by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression and constitutes up to 20% of all breast cancers cases. TNBCs account for a disproportionate number of deaths from breast cancer, especially among premenopausal African-American and Hispanic women. High mortality rates among TNBC patients can partly be attributed to a propensity to develop distant metastases within 5-years of diagnosis, despite the use of systemic chemotherapy. The mechanisms underlying this propensity for metastases noted with TNBC remain poorly understood. Unlike other subtypes of breast cancer, there are currently no targeted agents approved to treat TNBCs, and the only option for patients is systemic chemotherapy with its inherent toxicities. Understanding mechanisms underlying the metastatic potential of TNBC can aid in the development of novel www.impactjournals.com/oncotarget therapies that reduce the number of deaths linked to this breast cancer subtype
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