Alternative Splicing in Breast Cancer and the Potential Development of Therapeutic Tools

Martínez-Montiel, Nancy; Anaya-Ruı́z, Maricruz; Pérez-Santos, Martín; Contreras, Rebeca Débora Martínez

doi:10.3390/genes8100217

Cited by 28 publications

(37 citation statements)

References 143 publications

(142 reference statements)

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“…Alternative splicing has recently been viewed as a new hall mark of cancer [50]. Research has now uncovered various alternative spliced isoforms implicated in breast cancer, including BRCA1, DMTF1, FGFR, HER2, KLF6, Survivin, and TP53 [51]. Abnormal expression of splice factors in cancer changes the alternative splicing of pre-mRNAs.…”

Section: Discussionmentioning

confidence: 99%

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

Leung

Tsoi

Gong

et al. 2020

Cancers

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Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.

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Section: Discussionmentioning

confidence: 99%

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

Leung

Tsoi

Gong

et al. 2020

Cancers

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“…Such splicing errors can lead to alterations in relative isoform expression of a particular mRNA or lead to an aberrant protein that has a change of function. A more detailed discussion on points 1 and 3 are detailed elsewhere ( Martinez-Montiel et al . 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Splicing dysregulation as a driver of breast cancer

Read¹,

Natrajan²

2018

Endocrine-Related Cancer

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Breast cancer is known to be a heterogeneous disease driven by a large repertoire of molecular abnormalities, which contribute to its diverse clinical behaviour. Despite the success of targeted therapy approaches for breast cancer patient management, there is still a lack of the molecular understanding of aggressive forms of the disease and clinical management of these patients remains difficult. The advent of high-throughput sequencing technologies has paved the way for a more complete understanding of the molecular make-up of the breast cancer genome. As such, it is becoming apparent that disruption of canonical splicing within breast cancer governs its clinical progression. In this review, we discuss the role of dysregulation of spliceosomal component genes and associated factors in the progression of breast cancer, their role in therapy resistance and the use of quantitative isoform expression as potential prognostic and predictive biomarkers with a particular focus on oestrogen receptor-positive breast cancer.

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“…We observed that A3B splicing events were more common in adjacent normal tissues compared to tumors of several types. This suggests that AS of A3B is an intrinsic, tissue-specific regulatory mechanism rather than a result of general dysregulation of splicing machinery in tumors 44,45 , 268 manifested in the inactivation of tumor suppressor genes and generation of tumor-specific isoforms 46 . 269…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific characterization implicates alternative splicing in APOBEC3B as a mechanism restricting APOBEC-mediated mutagenesis

Banday¹,

Onabajo²,

Lin³

et al. 2020

Preprint

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APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis, but the understanding of the regulation of their mutagenic activity remains limited. Here, we showed that mutagenic and non-mutagenic A3A and A3B enzymes are produced by canonical and alternatively spliced A3A and A3B isoforms, respectively. Notably, increased expression of the canonical A3B isoform, which encodes the mutagenic A3B enzyme, predicted shorter progression-free survival of bladder cancer patients. Expression of the mutagenic A3B isoform was reduced by exon 5 skipping, generating a non-mutagenic A3B isoform. The exon 5 skipping, which was dependent on the interaction between SF3B1 splicing factor and weak branch point sites in intron 4, could be enhanced by an SF3B1 inhibitor, decreasing the production of the mutagenic A3B enzyme. Thus, our results underscore the role of A3B, especially in bladder cancer, and implicate alternative splicing of A3B as a mechanism and therapeutic target to restrict APOBEC-mediated mutagenesis.

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Alternative Splicing in Breast Cancer and the Potential Development of Therapeutic Tools

Cited by 28 publications

References 143 publications

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2

Splicing dysregulation as a driver of breast cancer

Isoform-specific characterization implicates alternative splicing in APOBEC3B as a mechanism restricting APOBEC-mediated mutagenesis

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