Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets

Varešlija, Damir; Priedigkeit, Nolan; Fagan, Ailís; Purcell, Siobhan; Cosgrove, Nicola; O’Halloran, Philip J.; Ward, Elspeth; Cocchiglia, Sinéad; Hartmaier, Ryan J.; Castro, Carlos; Zhu, Li; Tseng, George C.; Lucas, Peter C.; Puhalla, Shannon; Brufsky, Adam; Hamilton, Ronald L.; Mathew, Aju; Leone, José Pablo; Basudan, Ahmed; Hudson, Lance; Dwyer, Róisín M.; Das, Sudipto; O’Connor, Darran P.; Buckley, Patrick G.; Farrell, Michael; Hill, Arnold D.; Oesterreich, Steffi; Lee, Adrian V.; Young, Leonie S.

doi:10.1093/jnci/djy110

Cited by 93 publications

(117 citation statements)

References 54 publications

(48 reference statements)

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“…To determine if these effects of ELF5 could be seen in metastases from endocrine resistant breast cancer cases we interrogated gene expression profiles of matched primary and Table. Panel B, overlap between ELF5-interacting proteins identified in at least one MCF7 ELF5 RIME replicate and those identified in mouse trophoblast cells [49], and ER RIME in MCF7 cells [34], revealing GRHL2 and KDM1A as potential common interactors. Gene lists show functional analysis using GSEA of interactors also present in ER RIME and not present in the IgG controls, full gene list provided in S2 Table. metastatic breast cancer from brain [50]. This tumour collection contained 7 ER+ cases, 2 of which, X4 and X72, showed a large increase in ELF5 expression in the metastasis compared to the matched primary ( Fig 6A).…”

Section: Elf5 Levels Are Higher In Hormone Resistant Brain Metastasesmentioning

confidence: 99%

“…ELF5 expression is increased in endocrine resistant metastases. Panel A, levels of ESR1 and ELF5 expression in ER+ matched primary (P) and brain metastases (M) normalised from data produced by Vareslija and colleagues[50]. Panel B, GSEA determined enrichment (NES) of gene sets comprising genes differentially expressed in MCF-7 cells due to induction of ELF5 (DE) or a subset with an ELF5 ChIP binding site with 10kb (DEgenes_ChIP).…”

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confidence: 99%

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ELF5 modulates the estrogen receptor cistrome in breast cancer

et al. 2020

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Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance.

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Section: Elf5 Levels Are Higher In Hormone Resistant Brain Metastasesmentioning

confidence: 99%

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confidence: 99%

ELF5 modulates the estrogen receptor cistrome in breast cancer

et al. 2020

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“…Thus, ontologies associated with PSD4 knock-out in MCF10A cells correlate with those of the progression of DCIS to IDC in patients. We also compared the PSD4 mRNA expression in metastatic samples versus the paired primary BC by taking advantage of a publicly available series of 29 matched metastasis/primary cancer pairs 34,35 . We found significant reduction of PSD4 expression in the metastatic samples ( Fig.8d), further corroborating the role of EFA6B loss in tumor invasion.…”

Section: Efa6b Expression Is Down Regulated In Human Clinical Bc Sampmentioning

confidence: 99%

“…Expression profiling was based on DNA microarrays and comparison of expression levels between DCIS and IDC was done using the Student's t-test. Second, we analyzed expression from 29 matched metastasis-primary BC pairs, collected through two data sets: TCGA 34 for 7 pairs, and Vareslija's study 35 for 22 pairs, all having been profiled using RNA-seq. The comparison of PSD4 expression levels between metastases and primary BC was done using the paired Mann-Whitney test.…”

Section: Transcriptomic Analysesmentioning

confidence: 99%

EFA6B regulates a stop signal for collective invasion in breast cancer

Fayad

Monserrat

Partisani

et al. 2020

Preprint

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Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes, however additional mutations provide selective advantages to the tumor cells to resist treatment and develop metastases, therefore identification of secondary mutations is of paramount importance. EFA6B (Exchange Factor for ARF6, B) expression is reduced in breast cancer. To study the pro-tumoral impact of the loss of EFA6B we have invalidated its gene in normal human mammary cells. We found that EFA6B knock-out triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal a new EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up new avenues for the treatment of invasive breast cancer.

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“…Brain metastases (BM) of solid tumors are the most frequent intracranial tumors and about 10-fold more common than primary brain tumors (5). Brain metastases are associated with severe neurological symptoms and abysmal prognosis compared with other metastatic sites (6). The primary tumors most often responsible for brain metastases are melanomas (5-20%), lung (36-64%), and breast cancers (15-25%) (7).…”

Section: Introductionmentioning

confidence: 99%

Prostate Specific Membrane Antigen expression in the vasculature of primary lung carcinomas associates with faster metastatic dissemination to brain

Ramanathan

Lehtipuro

Sihto

et al. 2019

Preprint

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Glioblastomas and brain metastases (BM) of solid tumors are the most common central nervous system neoplasms associated with very unfavorable prognosis. In this study, we report the association of Prostate Specific Membrane Antigen with various clinical parameters in a large cohort of primary and secondary brain tumors. A tissue micro array containing 371 cases of ascending grade gliomas pertaining to astrocytic origin, samples of 52 cases of primary lung carcinomas with matching brain metastases with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in brain metastases arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumor cell expression. This result corroborated with the results obtained from the in silico (cancer genome databases) analyses. In the matched primary lung cancers and their brain metastases (n = 52), vascular PSMA expression in primary tumors led to significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report the vascular expression of PSMA in the primary and secondary brain tumors that globally associates with the malignant progression and poor outcome of the patients.

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Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets

Cited by 93 publications

References 54 publications

ELF5 modulates the estrogen receptor cistrome in breast cancer

ELF5 modulates the estrogen receptor cistrome in breast cancer

EFA6B regulates a stop signal for collective invasion in breast cancer

Prostate Specific Membrane Antigen expression in the vasculature of primary lung carcinomas associates with faster metastatic dissemination to brain

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