Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53-independent pathway

Abstract

The Cancer Genome Atlas (TCGA) data indicate that high MDM2 expression correlates with all subtypes of breast cancer. Overexpression of MDM2 drives breast oncogenesis in the presence of wild-type or mutant p53 (mtp53). Importantly, estrogen-receptor positive (ER+) breast cancers overexpress MDM2 and estrogen mediates this expression. We previously demonstrated that this estrogen-MDM2 axis activates the proliferation of breast cancer cell lines T47D (mtp53 L194F) and MCF7 (wild-type p53) in a manner independent of increased degradation of wild-type p53 (ie, p53-independently). Herein we present data supporting the role of the estrogen-MDM2 axis in regulating cell proliferation and mammary tissue architecture of MCF7 and T47D cells in a p53-independent manner. Inducible shRNA mediated MDM2 knockdown inhibited colony formation in soft agar, decreased mass size and induced lumen formation in matrigel and also significantly reduced mitosis as seen by decreased phospho-histone H3 positive cells. The knockdown of MDM2 in both cell lines decreased Rb phosphorylation and the level of E2F1 protein. This signaling was through the estrogen receptor because fulvestrant (a selective estrogen receptor degrader) decreased MDM2 protein levels and decreased phosphorylation of Rb. Taken together these data indicate that in some ER+ breast cancers the estrogen-MDM2-Rb-E2F1 axis is a central hub for estrogen-mediated p53-independent signal transduction. This is the first indication that estrogen signaling utilizes the estrogen-MDM2 axis to provoke phosphorylation of Rb and increase E2F1 while promoting abnormal mammary architecture.

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

“…Mouse double minute 2 homolog (MDM2) is a protein that negatively regulates p53 activity, in destabilizing and inhibiting cellular senescence . Approximately 20%–30% of breast cancer patients show overexpression of MDM2, and this overexpression contributes particularly to the progression of HR‐positive breast cancer . It is reported that CDK4/6 inhibitor‐resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence .…”

“…53 Approximately 20%-30% of breast cancer patients show overexpression of MDM2, 54 and this overexpression contributes particularly to the progression of HR-positive breast cancer. 55 It is reported that CDK4/6 inhibitor-resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence. 56 Therefore, interruption of the senescence pathway by MDM2 in a p53-dependent manner may cause resistance to CDK4/6 inhibitors.…”

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].…”

Hematopoietic Substrate-1-Associated Protein X-1 Regulates the Proliferation and Apoptosis of Endothelial Progenitor Cells Through Akt Pathway Modulation

“…However, p53 degraded much more slowly and the ubiquitination of p53 was remarkably decreased after HAX‐1 was knocked out. It is well known that as a negative regulator of p53, MDM‐2 could ubiquitinate p53 to promote degradation , and the activation of MDM‐2 is regulated by phosphokinase Akt1, which could phosphorylate MDM‐2 at Ser186 to enhance its ubiquitination‐promoting function . Similarly, the activity of Akt1 is also regulated by phosphorylation at Thr 308 and Ser 473 .…”