Abstract
The annexin family and S100A associated proteins are important regulators of diverse calcium-dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.
Highlights
Breast cancer sub-types are defined by their molecular heterogeneity and pathological profiles and therapeutic options, response to treatment, and prognosis are based on the diagnosis and classification of tumors into one of the different sub-types [1]
To further explore the underlying mechanisms that lead to cell cycle arrest and metabolic/phenotypic changes we used SILAC LC-MS/MS methodology to determine the proteomic profile of MCF-7 cells post activation of p14ARF-p53 at 24 h and 72 h
To determine if annexin expression was regulated by p53 in other cell types, we examined the effects of p53 activation in two distinct and functionally different cell lines, U2OS, an osteosarcoma cell line and MCF-7 breast cancer cells
Summary
We aimed to assess how p53 induced upregulation of annexin/S100A would affect the following clinical outcomes: Relapse Free Survival (RFS), Distant Metastasis Free Survival (DMFS), and Overall Survival (OS), both in untreated and treated ER+ breast cancer patients
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