The nuclear receptor coactivator AIB1/SRC-3 is required for HER (EGFR/Neu)-mediated signaling in cancer
The nuclear receptor coactivator AIB1 (Amplified in Breast Cancer 1) was initially defined as a transcriptional coactivator of hormone-bound nuclear receptors. However, a recent growing body of evidence has established a role for AIB1/SRC-3 in growth factor-induced tumor progression, independent of hormone activity. The human epidermal growth factor receptor HER/EGFR family of tyrosine kinase receptors have been implicated in the progression of a wide variety of human cancers. Extracellular activation of the HER family members leads to the activation of mitogenic kinase pathways that drive tumorigenesis. Initial studies from our lab show that AIB1/SRC-3 potentiates EGF-induced gene transcription and signaling. We also discovered that AIB1/SRC-3 is highly amplified and overexpressed in pancreatic adenocarcinoma, a malignancy strongly associated with EGFR overexpression and signaling. Clinical studies have reported that the overexpression of HER2/Neu, a HER/EGFR family member, is correlated with high AIB1/SRC-3 mRNA levels in primary breast tumors. Furthermore, the overexpression of AIB1/SRC-3 and HER2/Neu in breast cancer patients is associated with tamoxifen resistance and poor disease-free survival. These findings suggest that AIB1/SRC-3 plays a role in hormone-independent signaling by increasing the sensitivity of cancer cells to EGFR/HER-driven tumorigenesis. However, a mechanistic relationship between AIB1/SRC-3 and the HER growth factor receptor family members has not been clearly defined.
This study addresses the interplay between AIB1/SRC-3 and the HER family members, EGFR and HER2/Neu. First, the role of AIB1/SRC-3 in EGF-induced signaling was determined using two widely-studied human PanCa cell lines, PANC-1 and COLO 357PL. PanCa cell lines were chosen as the model to study the role of AIB1/SRC3 in growth factor signaling due to the absence of ER and PR as well as high expression of EGFR and AIB1/SRC-3. It was found that the reduction of AIB1/SRC-3 levels in these cell lines using siRNA reduced EGF-induced phosphorylation of c-Jun-N-terminal kinase (JNK), resulting in decreased cell proliferation and anchorage-independent colony formation.
Findings from the in vitro studies led to the in vivo investigation of AIB1/SRC3's role in the progression of HER2/ Neu driven mammary cancer. This was assessed through the generation of MMTV-Neu/SRC-3wt, MMTV-Neu/SRC-3 +/-, and MMTV-Neu/SRC-3-/- mice. The deletion of SRC-3 significantly abrogated Neu-induced mammary tumorigenesis through a reduction in phospho-Neu activation, mitogenic signaling and mammary epithelial cell proliferation. Overall, both of these studies provide direct evidence supporting a role for AIB1/SRC-3 in EGFR and HER2/Neu mediated tumorgenesis.