Her2/EGFR-PDGFR pathway aberrations associated with tamoxifen response in metastatic breast cancer patients

Abstract

Background Metastatic breast cancer (MBC) is a major health problem worldwide. Some patients improve on tamoxifen and others do not respond to treatment. Therefore, the aim of the current study is to assess genetic aberrations in the Her2/EGFR-PDGFR pathway associated with tamoxifen response in MBC patients. Methods This is a retrospective cohort study, including 157 hormone receptors positive, locally recurrent inoperable and/or MBC patients on tamoxifen treatment. Patients were categorized into 78 (49.7%) tamoxifen responders and 79 (50.3%) tamoxifen non-responder patients. Genetic aberrations of 84 genes involved in the Her2/EGFR-PDGFR pathway were assessed in the tumor tissue samples obtained from the patients using SA-Bioscience assay. The identified panel was correlated to patients’ response to treatment, to detect the differentially expressed genes in tamoxifen responders and non-responders. Results One hundred twenty-three (78.3%) patients were estrogen receptor (ER) and progesterone receptor (PR) positive, 108 (68.8%) were ER only positive, and 78 (49.7%) were PR only positive. There were 56 genes overexpressed in the refractory group compared to responders. However, only five out of these 56 genes, Janus kinase 1 (JAK1), collagen type I alpha 1 (COL1A1), GRB2-associated binding protein 1 (GAB1), fibronectin-1 (FN1), and MAP kinase-interacting serine/threonine-protein kinase (MKNK1), showed statistical significance between the two groups. Patients with bone metastasis showed a better response to treatment compared to those with metastatic deposits in other sites such as visceral metastasis (P < 0.005). Conclusions Genetic profiling using simple quantitative real-time polymerase chain reaction (qRT-PCR) protocols could be used to assess response to tamoxifen treatment in MBC patients. According to our data, a five-gene panel in the EGFR pathway (JAK1, COL1A1, GAB1, FN1 and MKNK1) could be used to categorize MBC patients into groups according to treatment response.

The Role of GAB1 in Cancer

“…On the other hand, GAB1 has been reported to be responsible for restoring PI3K/AKT1 pathway activation in HGF-induced resistance to MET inhibitors (JNJ-38877605, PHA-665752, crizotinib) and anti-MET antibody (DN30 Fab) [ 136 ]. GAB1 is associated with tamoxifen resistance in metastatic breast cancer patients [ 137 ]. Furthermore, it has been reported that chronic lymphocytic leukemia (CLL) cells treated with ibrutinib lead to an increase in GAB1 mRNA and protein levels.…”

Synthesis, Characterization, and Anticancer Activity of New N,N′-Diarylthiourea Derivative against Breast Cancer Cells

“…Worldwide, breast cancer (BC) has an incidence rate of 11.7% (2,261,419 new cases), just slightly greater than the prevalence of lung cancer (11.4%) [1]. Among all cancers, breast cancer is one of the most common, representing 32% of cases in the latest information available from Egypt's NCRP, the National Cancer Registry Programme [2]. Despite high survival rates in many developed nations, recent data show that Egypt's has remained dismal, especially when measured over a period of five years [3].…”