GSE140758 Synergistic targeting of estrogen-receptor positive breast cancers by MDM2 inhibition in combination with endocrine therapy or CDK4/6 inhibition

Contributors : Heloisa H Milioli ; Neil PortmanSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensHere we characterise the response of models of ER-positive breast cancer to treatment with the small molecule MDM2 inhibitor NVP-CGM097, a dihydroisoquinolinone derivative currently evaluated in a phase I clinical trial. We show that NVP-CGM097 reduces tumour cell viability of in vitro and in vivo models of endocrine sensitive, endocrine resistant and palbociclib (CDK4/6 inhibitor) resistant p53 wildtype (p53wt) ER-positive breast cancer. NVP-CGM097 synergises with both fulvestrant and palbociclib in models of therapy resistance. Importantly, we identify the key mechanisms of the synergistic interactions between NVP-CGM097 and endocrine therapy, which occurs through the inhibition of E2F Targets and G2M Checkpoint signalling and induction of senescence, rather than depending upon upregulation of p53 dependent apoptotic pathways. Moreover, we find these same pathways are synergistically targeted during the combination treatment of ER positive breast cancer models with NVP-CGM097 and palbociclib. This indicates the genuine potential of MDM2 inhibition as therapy in advanced ER-positive breast cancer as combination endocrine therapy and CDK4/6 inhibitor treatment becomes embedded as standard of care.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research

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shi Inoue Long noncoding RNAs (lncRNAs) are defined as RNAs longer than 200 nucleotides that do not encode proteins. Recent studies have demonstrated that numerous lncRNAs are expressed in humans and play key roles in the development of various types of cancers. Intriguingly, some lncRNAs have been demonstrated to be involved in endocrine therapy resistance for breast cancer through their own mechanisms, suggesting that lncRNAs could be promising new biomarkers and therapeutic targets of breast cancer. Here, we summarize the functions and mechanisms of lncRNAs related to the endocrine therapy resistance of breast cancer.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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Source: Cancer Chemotherapy and Pharmacology - Category: Cancer & Oncology Source Type: research
Abstract Tamoxifen (TAM), the most widely used anti-estrogenic drug, inhibits the progression of breast cancer through competing with estrogen for binding to the estrogen receptor (ER). Tamoxifen has been the first-line adjuvant endocrine therapy in pre- and postmenopausal patients with ER + breast cancer for two decades. However, due to its side effects, interest in using anticancer agents derived from natural foods has increased. It has recently been stated that some probiotics can improve the efficacy of anticancer drugs via synergistic effects. Here, Local Probiotic Lactobacillus Brevis were isol...
Source: Nutrition and Cancer - Category: Cancer & Oncology Authors: Tags: Nutr Cancer Source Type: research
AbstractPurpose of ReviewCyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2 −) metastatic breast cancer (MBC). However, optimal therapy after CDK4/6 inhibitors is unknown. This review provides an update on recent understanding of potential resistance mechanisms to CDK4/6 inhibitors and therapeutic strategies.Recent FindingsCDK4/6 inhibitors are broadly effective for HR+/HER2 − MBC. However, intrinsic and acquired resistance is inevitable. Although there are no established clinical predictors o...
Source: Current Oncology Reports - Category: Cancer & Oncology Source Type: research
Conclusions: In total, the current findings from this work add substantially to the understanding of ESR1's molecular regulatory mechanism in ERα positive breast cancer.
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Authors: Carausu M, Melaabi S, Pierga JY, Bidard FC, Cabel L Abstract ESR1 mutation is frequently encountered in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), especially after aromatase inhibitor (AI) therapy, as a mechanism of resistance to endocrine therapy. Circulating tumor DNA-based detection of ESR1 mutation in plasma has been demonstrated as a prognostic and predictive factor for poor outcomes in subsequent AI therapy. In this case report, for the first time, we describe the detection of ESR1 mutation (p.Tyr537Ser) only in the cerebro...
Source: Journal of Breast Cancer - Category: Cancer & Oncology Tags: J Breast Cancer Source Type: research
Conclusion: We propose a cut-off value of 35% to best predict RFS in patients with surgically resected breast cancer. AR expression was positive in 68.4% of patients, and AR positivity was found to be an independent prognostic factor for longer RFS. PMID: 32395377 [PubMed]
Source: Journal of Breast Cancer - Category: Cancer & Oncology Tags: J Breast Cancer Source Type: research
Authors: Huang L, Liang G, Zhang Q, Zhao W Abstract As a standard treatment, endocrine therapy has dramatically enhanced the prognosis of patients with estrogen receptor (ER)-positive breast cancer, which accounts for nearly 70% of all breast cancers. Antiestrogen drugs such as tamoxifen and aromatase inhibitors are the standard treatment options for ERα-positive breast cancer. However, acquired antiestrogen resistance is still the leading cause of disease recurrence and progression. Evidence has shown that long noncoding RNAs (lncRNAs) play an essential role in the development of antiestrogen resistance in E...
Source: Journal of Breast Cancer - Category: Cancer & Oncology Tags: J Breast Cancer Source Type: research
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Source: General Thoracic and Cardiovascular Surgery - Category: Cardiovascular & Thoracic Surgery Source Type: research
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Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
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