Abstract
MDM2 and MDM4 are heterodimeric, non-redundant oncoproteins that potently inhibit the p53 tumor suppressor protein. MDM2 and MDM4 also enhance the tumorigenicity of breast cancer cells in in vitro and in vivo models and are overexpressed in primary human breast cancers. Prior studies have characterized Estrogen Receptor Alpha (ERα/ESR1) as a regulator of MDM2 expression and an MDM2- and p53-interacting protein. However, similar crosstalk between ERα and MDM4 has not been investigated. Moreover, signaling pathways that mediate the overexpression of MDM4 in human breast cancer remain to be elucidated. Using the Cancer Genome Atlas (TCGA) breast invasive carcinoma patient cohort, we have analyzed correlations between ERα status and MDM4 and MDM2 expression in primary, treatment-naïve, invasive breast carcinoma samples. We report that the expression of MDM4 and MDM2 is elevated in primary human breast cancers of luminal A/B subtypes and associates with ERα-positive disease, independently of p53 mutation status. Furthermore, in cell culture models, ERα positively regulates MDM4 and MDM2 expression via p53-independent mechanisms, and these effects can be blocked by the clinically-relevant endocrine therapies fulvestrant and tamoxifen. Additionally, ERα also positively regulates p53 expression. Lastly, we report that endogenous MDM4 negatively regulates ERα expression and forms a protein complex with ERα in breast cancer cell lines and primary human breast tumor tissue. This suggests direct signaling crosstalk and negative feedback loops between ERα and MDM4 expression in breast cancer cells. Collectively, these novel findings implicate ERα as a central component of the p53-MDM2-MDM4 signaling axis in human breast cancer.
Highlights
MDM2/HDM2 and MDM4/MDMX/HDMX are homologous, heterodimeric, E3-ubiquitin protein ligases that are classically known for their non-redundant abilities to inhibit the p53 tumor suppressor protein p53 regulates a variety of cellular processes, including DNA repair, apoptosis, cell cycle arrest, senescence, autophagy and metabolism, amongst others
We utilized The Cancer Genome Atlas invasive breast carcinoma (TCGA BRCA) RNA-Seq gene expression dataset to analyze the expression of MDM4 and MDM2 mRNA in treatment-naive primary human breast invasive carcinoma samples
We observed that MDM4 and MDM2 mRNA expression was elevated in primary breast invasive carcinomas of luminal A and luminal B molecular subtypes, as compared to HER2enriched, basal, and normal-like subtypes (Figure 1, panels A and B)
Summary
MDM2/HDM2 and MDM4/MDMX/HDMX are homologous, heterodimeric, E3-ubiquitin protein ligases that are classically known for their non-redundant abilities to inhibit the p53 tumor suppressor protein (reviewed in [1,2,3,4]) p53 regulates a variety of cellular processes, including DNA repair, apoptosis, cell cycle arrest, senescence, autophagy and metabolism, amongst others (reviewed in [5,6,7,8,9]). Consistent with its oncogenic role, the MDM2 gene is overexpressed at the mRNA and protein levels in 26-73% of primary human breast cancers [47, 49,50,51,52,53,54]. Since MDM2 gene amplifications are relatively infrequent [45, 52, 53, 55,56,57,58], the overexpression of MDM2 in breast cancer is likely mediated by aberrant gene regulation
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