Role of IRS1 and IRS2 in Modulating ErbB-induced Tumorigenesis

Previous studies suggested that the adapter proteins IRS1 and IRS2 may interact with ErbB1 or ErbB2 receptors. However, we could not clearly decipher a role of IRSs in ErbB2 induced tumorigenesis. We expanded our research to the IGF-IR receptor for which IRSs serve as the main adapter proteins for downstream signaling. In addition, IGF-IR is a promising target for anti-cancer therapy. Up to date, little is known about biomarkers for response to IGF-IR and subsequent sensitivity to IGF-IR therapy. Furthermore, it is important to identify a patient population who is most likely to benefit from IGF-IR therapy. We previously reported an IGF-I gene expression signature, based upon genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. Confirming that this signature can measure IGF activity, we found that the signature was reversed in three different models cancer cell lines or xenografts treated with three different anti-IGF-IR therapies. We originally reported that the IGF signature was present in triple-negative human breast cancers TNBC, and found here that the signature is similarly present in TNBC cell lines. Especially TNBC cell lines were 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 palpablreduced proliferation, increased apoptosis, and mi