Role of IRS1 and IRS2 in Modulating ErbB-induced Tumorigenesis
Abstract
Previous studies suggested that the adapter proteins IRS1 and IRS2 may interact with ErbB1 or ErbB2 receptors. However, I found that overexpression of IRS2 didn't affect ErbB2-induced tumorigenesis or metastasis. Supporting this, I failed to find an association between ErbB2 and IRSs in breast cancer cells. I thus expanded my studies to the IGF-IR receptor for which IRSs serve as the main adapter proteins for downstream signaling. I performed reverse phase proteomic analysis of IGF-I and insulin action in 23 breast cancer cell lines. We found that IRS-1 is a central signaling node in the IGF-IR signaling pathways, and it needs to be inhibited for optimal pathway blockade. Finally, I studied the role of an IGF-I gene signature in predicting response to an IGF-IR inhibitor. I confirming that this signature can measure IGF activity, as it was reversed in three different models (cancer cell lines or xenografts) treated with three different anti-IGF-IR therapies. We found that the IGF signature is present in triple negative breast cancer (TNBC) cell lines, which were especially sensitive to an IGF-IR tyrosine kinase inhibitor (BMS-754807). Consistent with this, comparative gene expression analysis among the most resistant and sensitive cell lines identified 114 differentially expressed genes which confirmed TNBC as being sensitive. Furthermore, sensitivity to BMS-754807 significantly correlated to expression of the IGF gene signature. Supporting a role for IGF-IR signaling in TNBC, the primary human TNBC tumorgraft MC1 showed high levels of IGF-IR expression, activity, and IGF gene signature score, and showed growth inhibition following treatment with BMS-754807 as a single agent, and in combination with docetaxel tumor regression occurred until no tumor was palpable. This regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. These studies have further highlighted a critical role for IRSs in IGF-IR action in breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2010
- Accession Number
- ADA541311
Entities
People
- Beate Litzenburger
Organizations
- Baylor College of Medicine