Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery

McDonnell, Donald P.; Norris, John D.; Chang, Ching‐yi

doi:10.1016/j.ccell.2018.01.014

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…Importantly, the Cdk7 inhibitor, which inhibits S118 phosphorylation, suppresses growth of MCF7 breast cancer cells expressing either wild-type or mutant ER. Further, recent data on constitutively phosphorylated ER at S118 [27] highlight the importance of this phosphorylation in drug-resistant metastatic disease. PKA and p21-activated kinases 1 (Pak1) phosphorylate the hinge region of ER at S305 [28], making ER unresponsive to tamoxifen.…”

Section: Er Signalling In Breast Cancermentioning

confidence: 99%

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

Amicis

Chimento

Montalto

et al. 2019

IJMS

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Extensive research over the past 25 years in hormone-dependent cancers, such as breast cancer and prostate cancer, has identified the molecular mechanisms driven by steroid receptors, elucidating the interplay between genomic and non-genomic steroid receptors mechanism of action. Altogether, these mechanisms create the specific gene expression programs that contribute to endocrine therapy resistance and cancer progression. These findings, on the bidirectional molecular crosstalk between steroid and growth factor receptors pathways in endocrine resistance, suggest the use of multi-target inhibitors together with endocrine therapies, for treating resistant disease. In this review we will discuss the novel understanding on the chemopreventive and anti-cancer activities of Resveratrol (3,5,4′-trihydroxy-stilbene) (RSV), a phytoalexin found in grapes acting on a plethora of targets. We will highlight Resveratrol effect on steroid receptors signalling and its potential use in the treatment of hormone-dependent cancer. Understanding the molecular mechanisms by which the bioactive compound influences cancer cell behaviour, by interfering with steroid receptors functional activity, will help to advance the design of combination strategies to increase the rate of complete and durable clinical response in patients.

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Section: Er Signalling In Breast Cancermentioning

confidence: 99%

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

Amicis

Chimento

Montalto

et al. 2019

IJMS

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“…Although pivotal in breast cancer biology and evolution, ESR1 and PIK3CA mutations clinically are simplistically dichotomized as mutated or wild type. On the other hand, preclinical data suggests that a more precise characterization of ESR1 and PIK3CA mutated variants may help improve our understanding of how these alterations and associated co-mutations drive resistance and clonal evolution [ 13 , 26 – 28 ]. In this study we retrospectively analyzed ctDNA samples from a cohort of 703 patients to more specifically investigate the role of ESR1 and PIK3CA codon variants and other oncogenic pathway alterations and their impact on the clinical phenotype of HR + HER2− MBC.…”

Section: Discussionmentioning

confidence: 99%

“…ESR1 537 was significantly associated with SNVs in the ER and RAF pathways and CNVs in the MYC pathway, while ESR1 538 was associated with SNVs in the cell cycle pathway. The selection of such co-occurring alterations could be the result of prior exposure to ET, suggesting that endocrine resistance may be an emerging property of cellular-wide genetic, epigenetic, and transcriptional phenomena, rather than the result of a single hit aberration [ 26 , 34 ]. Multiparametric characterizations are therefore needed to better describe this phenomenon and select new therapeutic strategies that could target alterations on a pathway level [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): comprehensive circulating tumor DNA (ctDNA) analysis

Gerratana,

Davis,

Velimirovic

et al. 2023

Breast Cancer Res

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Background although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice. Methods The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored. Results The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases. Conclusions The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making.

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Mechanisms of resistance to estrogen receptor modulators in ER+/HER2− advanced breast cancer

Zhang

Wang

et al. 2019

Cell. Mol. Life Sci.

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Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery

Cited by 4 publications

References 10 publications

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): comprehensive circulating tumor DNA (ctDNA) analysis

Mechanisms of resistance to estrogen receptor modulators in ER+/HER2− advanced breast cancer

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