The role of MDM2 and MDM4 in breast cancer development and prevention

Abstract

The major cause of death from breast cancer is not the primary tumour, but relapsing, drug-resistant, metastatic disease. Identifying factors that contribute to aggressive cancer offers important leads for therapy. Inherent defence against carcinogens depends on the individual molecular make-up of each person. Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family: comprised of the proteins MDM2 and MDM4. In normal, healthy adult cells, the MDM family functions to critically regulate measured, cellular responses to stress and subsequent recovery. Proper function of the MDM family is vital for normal breast development, but also for preserving genomic fidelity. The MDM family members are best characterized for their negative regulation of the major tumour suppressor p53 to modulate stress responses. Their impact on other cellular regulators is emerging. Inappropriately elevated protein levels of the MDM family are highly associated with an increased risk of cancer incidence. Exploration of the MDM family members as cancer therapeutic targets is relevant for designing tailored anti-cancer treatments, but successful approaches must strategically consider the impact on both the target cancer and adjacent healthy cells and tissues. This review focuses on recent findings pertaining to the role of the MDM family in normal and malignant breast cells.

Expression profiling of genes modulated by rosmarinic acid (RA) in MCF-7 breast cancer cells

“…This process has been observed in various types of cancer, e.g. overexpression of MDM2 occurs in some types of breast cancer [22]. MDM2 has been also reported to negatively affect some other tumor suppressors, like SIRT6 or ERβ [22].…”

“…We observed a decrease of the MDM2 gene expression in cells treated with RA in different concentrations. The MDM2 gene encodes a ring finger domain-containing protein MDM2, which belongs to mouse double minute (MDM) family [22]. This protein is a negative regulator of p53 tumor suppressor which binds and ubiquitinates p53, resulting in its easier proteasomal degradation [23].…”

“…overexpression of MDM2 occurs in some types of breast cancer [22]. MDM2 has been also reported to negatively affect some other tumor suppressors, like SIRT6 or ERβ [22]. Therefore, inhibitors of the MDM2 pathway have attracted much attention of various researchers.…”

Tumour suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma cells

“…The major causes of death from breast cancer are due to relapse, drug-resistance and metastasis, which are highly related to the dysregulation of the mouse double minute (MDM) family [41][42][43] The MDM family comprises the E3 ligase MDM2 and its close homologue MDM4 (alternatively termed MDMX). MDM2 is a vital regulator of tumour suppressor p53 activity in the breast, [7,8,44] and has been identified as an independent prognostic biomarker in BC [45].…”

The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies

“…The pathways that allow stress-induced inhibition of MDM2 are essential to activate the cell growth suppressive activity of p53 [51]. Failures in the pathways that control MDM2 switch-off have been linked to cancer development [52,53].…”