Abstract 2100: Using in vitro models to identify newly synthesised proteins involved in the progression of breast cancer
Authors: Mahdi Amira F. , Malacrida Beatrice , McGourty Kieran , Lowery Aoife J. , Kiely Patrick A. 
Published: August 2018

Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer defined by tumours deficient in the expression of the three main immuno-histochemical markers: the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (HER2). Although accounting for only 15-20% of total breast cancer, TNBC is characterized by an aggressive phenotype and poor prognosis. As a result, it is the cause of a disproportionate amount of breast cancer deaths, with a higher incidence amongst younger women and ethnic minorities. In addition, lack of ER, PR and HER2 expression means there are no specific targeted therapies available. Significant efforts are being made to improve detection and survival rates for women affected by this disease. In order to achieve this, there is an urgent need to identify novel biomarkers and molecular targets so that we can more quickly and accurately diagnose breast cancer and develop a better understanding of disease progression in patients diagnosed with TNBC.

Genomic studies of patients with TNBC have shown that there is strong heterogeneity within the sub-type and a need for more precise classification at a molecular level. One target that has emerged from these studies is the epidermal growth factor receptor (EGFR). The EGFR is found to be over expressed in approximately 50% of TNBC cases and amplification of the EGFR gene is correlated with poor prognosis. Our study aims to investigate exactly how the progression of TNBC is influenced by specific micro-environmental cues and identify novel targets involved in the growth and migration of tumour cells.

We are investigating this target by developing cell culture based, in vitro models of EGFR driven cancer metastasis. Using Click-iT chemistry and mass spectrometry analysis, and by culturing the cells in both 2D and 3D in vitro models, we have identified proteins that are newly synthesised by the cancer cells as they are stimulated to migrate towards epidermal growth factor (EGF). Our approach has generated a list of proteins that span a myriad of different functions known to be important in cancer progression such as cell metabolism, intracellular calcium sensing, anti-oxidation and regulation of cell structure. We hypothesise that these newly synthesised proteins play a vital role in cancer cell migration and metastasis. Interaction and molecular function analysis of this list using STRING has shown an enrichment in calcium ion binding proteins. We are particularly interested the role of these calcium-regulated proteins in influencing the structure and behaviour of migrating cells. Currently, we are investigating the role of several of these proteins in regulating the cells response to the tumour microenvironment.

Directing pharmacological interventions towards these newly synthesised proteins has the potential to target invasive cancer cells and provide a highly specific and effective therapy for TNBC.

Citation Format: Amira F. Mahdi, Beatrice Malacrida, Kieran McGourty, Aoife J. Lowery, Patrick A. Kiely. Using in vitro models to identify newly synthesised proteins involved in the progression of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2100.