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

The major cause of death from breast cancer is not the primary turnout, 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 relerant for designing tailored anti-cancer treatments, but successful approaches must strategically consider the impact on both the target cancer and adjacent healthy ceils and tissues. This review focuses on recent findings pertaining to the role of the MDM family in normal and malignant breast cells.

Triple combination targeting PI3K,ER,and CDK4/6 inhibits growth of ER-positive breast cancer resistant to fulvestrant and CDK4/6 or PI3K inhibitor

Dear Editor,Despite the improved outcome of advanced estrogen receptor-positive(ER+)breast cancer patients treated with endocrine therapy in combination with either a cyclindependent kinase 4/6 inhibitor(CDK4/6i)or a phosphoinositide 3-kinase inhibitor(PI3Ki),the disease will eventually progress,and the optimal treatment strategy upon progression remains undefined[1-4].To address this,we developed MCF-7-and T47D-derived PIK3CAmutated breast cancer cell lines[5]resistant to combined CDK4/6i palbociclib and fulvestrant(MPF-R and TPFR)or combined PI3Ki alpelisib and fulvestrant(MAF-R and TAF-R),respectively(Supplementary Materials and Methods).Drug-sensitive isogenic cells(M-S and T-S)grown in parallel with MPF-R and TPF-R cells and the original MCF-7/S0.5 and T47D cells were analyzed for comparison.