AnxA2 contributes to TNBC progression




Gibbs, Lee D.
Vishwanatha, Jamboor


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Purpose: The National Cancer Institute (NCI) estimates that in 2015, approximately 232,340 women will be diagnosed with new cases of invasive breast cancer and 39,620 will succumb to the disease. Advances in breast cancer research have led to the identification of four molecular subtypes; Luminal A, Luminal B, Triple negative/basal-like, and HER2 (Human Epidermal Growth Factor [Erbb2]) type. Triple-negative breast cancers (TNBC) are identified by the absence of three major receptors that drive most breast cancer: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2); and constitutes 15 to 20% of diagnosed breast cancers. Given the heterogeneity and lack of standard molecular targets, patients with TNBC do not benefit from currently available targeted therapy, such as endocrine or anti-HER2 agents. Therefore, the only systemic treatment option available for these patients is surgery (+/- radiation) and chemotherapy with standard cytotoxic agents. Overall, TNBC is associated with poor prognosis, high mortality rate, and shorter median time to relapse (due to its aggressive tumor phenotype(s)), high recurrence rate, and visceral metastatic spread to the brain and lungs. This presents an urgent clinical need to identify new biomarker(s) that can be used for diagnosis and/ or as potential therapeutic targets. Our previous studies have demonstrated that AnxA2 is abundantly expressed in TNBC and has a reciprocal relationship with HER2 (Human Epidermal Growth Factor Receptor 2/ErBb2) at mRNA and protein levels. We have also demonstrated that AnxA2 and EGFR interact at the cell surface and this association is essential for EGFR mediated downstream signaling events that lead to cancer cell proliferation and migration. Furthermore, we have found that addition of growth factors, like EGF, stimulate the expression of AnxA2 at the mRNA and protein level in cancer cells expressing EGFR and basal levels of AnxA2. Based on our previous published studies and new preliminary data we hypothesize that AnxA2 expression in TNBC provides a selective advantage for TNBC fueling cancer progression. Our investigation will allow us to identify the AnxA2-EGFR relationship as a molecular contributor to TNBC progression. Materials and Methods: We serum starved MCF-7 cells overnight and treated with EGF (100ng/mL) at different time intervals. Increased expression of AnxA2 was observed at 48 and 72 hours at the protein level and mRNA. Membrane and cytosolic extraction of metastatic TNBC cell lines was performed for analysis of AnxA2 protein expression. TCGA(The Cancer Genome Atlas) analysis of breast cancer subtypes from clinical samples will also performed for analysis of AnxA2 and EGFR expression in cancer progression. Results: Our data indicate that increased expression of AnxA2 was observed at 48 and 72 hours at the protein level and mRNA fold change increased exponentially with EGF treatment. TCGA analysis unveils a significant increase in AnxA2 mRNA expression in comparison with other breast cancer subtypes. Conclusions: Our results suggest that AnxA2 increased expression during EGF stimulation of cancer cells with low expression of AnxA2 may be a potential mechanism of the AnxA2-EGFR interaction in TNBC. Increased expression of AnxA2 in TNBC in comparison with other breast cancer subtypes from the TCGA portal demonstrates AnxA2 as a potential biomarker for TNBC.