<scp>Fusion‐associated</scp>carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

Loo, Suet Kee; Yates, Megan E.; Yang, Sichun; Oesterreich, Steffi; Lee, Adrian V.; Wang, Xiaosong

doi:10.1002/gcc.23029

Cited by 15 publications

(11 citation statements)

References 119 publications

(259 reference statements)

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“…These include fusion proteins associated with ER such as ESR1-CCDC170 ( 73 – 75 ), and ESR1-YAP1 ( 76 ) and non ER related fusions such as CTNNBL1-RAF1, ACTL6A-PIK3CA, S6KCI-AKT3 ( 71 ), SEC16A-NOTCH1 ( 77 ), SEC22B-NOTCH2 ( 72 ), and ETV6-NTRK3 ( 78 ). A number of these fusions promote tumor growth, and patients expressing these fusion proteins have more rapid disease progression and shorter survival than fusion-negative patients ( 70 , 71 , 75 , 79 ). Identifying the full spectrum of the ESR1 gene fusions and characterizing their role in intrinsic ET resistance is critical for developing novel and effective targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

ESR1 fusions and therapeutic resistance in metastatic breast cancer

Nagy

Jeselsohn

2023

Front. Oncol.

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Breast cancer is the most frequent female malignant tumor, and the leading cause of cancer death in women worldwide. The most common subtype of breast cancer is hormone receptor positive that expresses the estrogen receptor (ER). Targeting ER with endocrine therapy (ET) is the current standard of care for ER positive (ER+) breast cancer, reducing mortality by up to 40% in early- stage disease. However, resistance to ET represents a major clinical challenge for ER+ breast cancer patients leading to disease recurrence or progression of metastatic disease. Salient drivers of ET resistance are missense mutations in the ER gene (ESR1) leading to constitutive transcriptional activity and reduced ET sensitivity. These mutations are particularly prominent and deleterious in metastatic breast cancer (MBC). In addition to activating ESR1 point mutations, emerging evidence imposes that chromosomal translocation involving the ESR1 gene can also drive ET resistance through the formation of chimeric transcription factors with constitutive transcriptional activity. Although these ESR1 gene fusions are relatively rare, they are enriched in ET resistant metastatic disease. This review discusses the characteristics of ER fusion proteins and their association with clinical outcomes in more aggressive and metastatic breast cancer. The structure and classification of ER fusion proteins based on function and clinical significance are also addressed. Finally, this review summarizes the metastatic phenotypes exhibited by the ER fusion proteins and their role in intrinsic ET resistance.

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Section: Introductionmentioning

confidence: 99%

ESR1 fusions and therapeutic resistance in metastatic breast cancer

Nagy

Jeselsohn

2023

Front. Oncol.

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“…Notably, a product of BCL2L14-ETV6 rearrangement promoted epithelial-mesenchymal transition and was associated with cell resistance to paclitaxel [ 65 ]. As ETV6 is a ubiquitously expressed transcriptional repressor, which was shown to form fusion genes with oncogenic consequences in a number of hematological malignancies and solid tumors [ 66 , 67 ], it would be crucial to determine whether BCL2L14-ETV6 fusion occurs in other types of cancer. In addition, a single nucleotide polymorphism variant of BCL2L14 (rs1544669) in former smokers was associated with a 36% increase in risk for lung cancer [ 68 ].…”

Section: Disease-associated Genetic Alterations Of Bcl2l14mentioning

confidence: 99%

BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

Hartman

Czyż

2023

Cell Death Differ

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Proteins from the BCL-2 family control cell survival and apoptosis in health and disease, and regulate apoptosis-unrelated cellular processes. BCL-Gonad (BCL-G, also known as BCL2-like 14) is a non-typical protein of the family as its long isoform (BCL-GL) consists of BH2 and BH3 domains without the BH1 motif. BCL-G is predominantly expressed in normal testes and different organs of the gastrointestinal tract. The complexity of regulatory mechanisms of BCL-G expression and post-translational modifications suggests that BCL-G may play distinct roles in different types of cells and disorders. While several genetic alterations of BCL2L14 have been reported, gene deletions and amplifications prevail, which is also confirmed by the analysis of sequencing data for different types of cancer. Although the studies validating the phenotypic consequences of genetic manipulations of BCL-G are limited, the role of BCL-G in apoptosis has been undermined. Recent studies using gene-perturbation approaches have revealed apoptosis-unrelated functions of BCL-G in intracellular trafficking, immunomodulation, and regulation of the mucin scaffolding network. These studies were, however, limited mainly to the role of BCL-G in the gastrointestinal tract. Therefore, further efforts using state-of-the-art methods and various types of cells are required to find out more about BCL-G activities. Deciphering the isoform-specific functions of BCL-G and the BCL-G interactome may result in the designing of novel therapeutic approaches, in which BCL-G activity will be either imitated using small-molecule BH3 mimetics or inhibited to counteract BCL-G upregulation. This review summarizes two decades of research on BCL-G.

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“…Gene fusion events involving ESR1 in breast cancer have been previously described, with one of the most common being a recurrent rearrangement between ESR1 (Chromosome 6q) exons 1-2 and its neighboring gene, coiled-coil domain containing 170 (ESR1-CCDC170) (23, 24). Identification of genomic structural rearrangements in ESR1 in metastatic breast cancer unveiled recurrent fusion transcripts at an ESR1 intron 6 translocation breakpoint (17).…”

Section: Introductionmentioning

confidence: 99%

Section: Main Text Introductionmentioning

confidence: 99%

ESR1fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes

Yates,

Li,

et al. 2023

Preprint

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Breast cancer is a leading cause of female mortality and despite advancements in diagnostics and personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. Fortunately, identification of mechanisms of therapeutic resistance have rapidly transformed our understanding of cancer evasion and is enabling targeted treatment regimens. When the druggable estrogen receptor (ER, ESR1), expressed in two-thirds of all breast cancer, is exposed to endocrine therapy, there is risk of somatic mutation development in approximately 30% of cases and subsequent treatment resistance. A more recently discovered mechanism of ER mediated endocrine resistance is the expression of ER fusion proteins. ER fusions, which retain the protein's DNA binding domain, harbor ESR1 exons 1-6 fused to an in-frame gene partner resulting in loss of the 3' ER ligand binding domain (LBD). In this report we demonstrate that in no-special type (NST) and invasive lobular carcinoma (ILC) cell line models, ER fusion proteins exhibit robust hyperactivation of canonical ER signaling pathways independent of the ligand estradiol or anti-endocrine therapies such as Fulvestrant and Tamoxifen. We employ cell line models stably overexpressing ER fusion proteins with concurrent endogenous ER knockdown to minimize the influence of endogenous wildtype ER. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably the MYC pathway. The heterogeneous 3' fusion partners, particularly transcription factors SOX9 and YAP1, evoked varying degrees of transcriptomic and cistromic activity that translated into unique phenotypic readouts. Herein we report that cell line activity is subtype-, fusion-, and assay-specific suggesting that the loss of the LBD, the 3' fusion partner, and the cellular landscape all influence fusion activity. Therefore, it will be critical to generate additional data on frequency of the ER fusions, in the context of the clinicopathological features of the tumor.

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Fusion‐associatedcarcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

Cited by 15 publications

References 119 publications

ESR1 fusions and therapeutic resistance in metastatic breast cancer

ESR1 fusions and therapeutic resistance in metastatic breast cancer

BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

ESR1fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes

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