ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

Li, Zheqi; McGinn, Olivia; Wu, Yang; Bahreini, Amir; Priedigkeit, Nolan; Ding, Kai; Onkar, Sayali; Lampenfeld, Caleb; Sartorius, Carol A.; Miller, Lori; Rosenzweig, Margaret; Cohen, Ofir; Wagle, Nikhil; Richer, Jennifer K.; Muller, William J.; Buluwela, Lakjaya; Ali, Simak; Bruno, Tullia C.; Vignali, Dario A.A.; Fang, Yusi; Zhu, Li; Tseng, George C.; Gertz, Jason; Atkinson, Jennifer M.; Lee, Adrian V.; Oesterreich, Steffi

doi:10.1038/s41467-022-29498-9

Cited by 36 publications

(28 citation statements)

References 123 publications

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“…S11A). Surprisingly, mining our MCF7 ESR1 mutant cell model ER ChIP-seq data (46) showed an absence of proximate Y537S or D538G mutant ER binding sites (± 50kb of TSS) at desmosome and connexon target gene loci. These results suggest that the We therefore hypothesized that these altered adhesion target genes might be regulated via a secondary downstream effect of the hyperactive mutant ER.…”

Section: Mutant Esr1 Cells Show Increased Desmosome Gene and Gap Junc...mentioning

confidence: 79%

HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

Yates

et al. 2022

Cancer Research

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Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell–cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation–modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer. Significance: Context- and allele-dependent transcriptome and cistrome reprogramming in mutant ESR1 cell models elicit diverse metastatic phenotypes related to cell adhesion and migration, which can be pharmacologically targeted in metastatic breast cancer.

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Section: Mutant Esr1 Cells Show Increased Desmosome Gene and Gap Junc...mentioning

confidence: 79%

HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

Yates

et al. 2022

Cancer Research

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“…Research linking ESR1 mutations and immune activation remains scarce. We reported previously that ESR1 mutant metastatic samples have higher levels of macrophages, and also proposed possible mechanisms including activation of innate immune response via STING pathways and production of CHI3L1 enhanced recruitment of macrophages via elevated S100A8/A9-TLR4 signaling 23 , 83 . Here we identified a further significantly increased level of total and PD-L1 positive macrophages in the rare tumors with co-occurring TP53 - ESR1 mutations.…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies have shown immune modulation in both TP53 and ESR1 mutant tumors 23 , 83 – 85 . First, it has been reported that specific p53 mutant variants such as R175H are associated with elevated macrophage recruitment 86 , 87 .…”

Section: Discussionmentioning

confidence: 95%

Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer

Sikora

Richer

et al. 2022

npj Breast Cancer

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Both TP53 and ESR1 mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity between TP53 and ESR1 mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay between TP53 and ESR1 mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features. ESR1 mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression in TP53 mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences of TP53 and ESR1 mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity between ESR1 and TP53 mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.

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“…Промоторы активных генов совпадают с областями открытого хроматина и демонстрируют характерный паттерн распределения нуклеосом [64] DNase-seq [65] MNase-seq [66] ATAC-seq [67] FAIRE-seq [68] Пространственная организация хромосом Энхансеры [69] и сайленсеры [54,61,70] физически взаимодействуют с промоторами при помощи петлевых контактов. Инсуляторы формируют петлевые домены, ограничивающие область действия энхансеров [71,72] HiC [73] ChIA-PET [74] HiChIP [75] PLAC-ChIP [76] www.clinpractice.ru химерного белка подавляется, а клетки, содержащие такую конструкцию, сохраняют жизнеспособность при химической индукции апоптоза. Таким образом, в пуле трансфицированных клеток выживают только несущие генетические конструкции, содержащие сайленсеры.…”

Section: массовый параллельный репортерный анализ для исследования ци...unclassified

Practical application of massively parallel reporter assay in biotechnology and medicine

Romanov

Laktionov

2023

Journal of Clinical Practice

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The development and functioning of an organism relies on tissue-specific gene programs. Genome regulatory elements play a key role in the regulation of such programs, and disruptions in their function can lead to the development of various pathologies, including cancers, malformations and autoimmune diseases. The emergence of high-throughput genomic studies has led to massively parallel reporter analysis (MPRA) methods, which allow the functional verification and identification of regulatory elements on a genome-wide scale. Initially MPRA was used as a tool to investigate fundamental aspects of epigenetics, but the approach also has great potential for clinical and practical biotechnology. Currently, MPRA is used for validation of clinically significant mutations, identification of tissue-specific regulatory elements, search for the most promising loci for transgene integration, and is an indispensable tool for creating highly efficient expression systems, the range of application of which extends from approaches for protein development and design of next-generation therapeutic antibody superproducers to gene therapy. In this review, the main principles and areas of practical application of high-throughput reporter assays will be discussed.

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ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

Cited by 36 publications

References 123 publications

HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer

Practical application of massively parallel reporter assay in biotechnology and medicine

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