Analysis of HER2-Low Breast Cancer in Aotearoa New Zealand: A Nationwide Retrospective Cohort Study.

Objectives: To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low, and HER2-zero invasive breast cancers in New Zealand. The study will reveal the proportion of women who may benefit from new HER2-targeted antibody drug conjugate (ADC) therapies.

Methods: Utilising data from Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period.

Combining TP53 mutation and isoform has the potential to improve clinical practice.

The clinical importance of assessing and combining data on TP53 mutations and isoforms is discussed in this article. It gives a succinct overview of the structural makeup and key biological roles of the isoforms. It then provides a comprehensive summary of the roles that p53 isoforms play in cancer development, therapy response and resistance.

Close Links between Cold Shock Proteins and Cancer.

Nine of the ten papers published in this Special Issue explore various aspects of the multifunctional protein Y-box binding protein-1 (YB-1) and its role in cancer [...

Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy.

Background: Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles of immunotherapy.

Method: A melanoma-specific ctDNA next-generation sequencing (NGS) panel, droplet digital polymerase chain reaction (ddPCR) and mass spectrometry analysis were used to identify ctDNA mutations in longitudinal blood plasma samples from Aotearoa New Zealand (NZ) patients receiving immunotherapy for melanoma.

Breast Cancer Patient Prognosis Is Determined by the Interplay between Mutation and Alternative Transcript Expression: Insights from Long Amplicon Digital PCR Assays.

The gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth reference transcript encoding ∆40p53α.

Intronic Polymorphisms Are Associated with Increased Transcript, Immune Infiltration and Cancer Risk.

We investigated the influence of selected SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.

Accessing a New Dimension in TP53 Biology: Multiplex Long Amplicon Digital PCR to Specifically Detect and Quantitate Individual Transcripts.

, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of alternative RNA splice forms and their use as clinical biomarkers has been hampered by limited specificity and quantitative accuracy of current methods.

Orthogonal assays for the identification of inhibitors of the single-stranded nucleic acid binding protein YB-1.

We have previously shown that high expression of the nucleic acid binding factor YB-1 is strongly associated with poor prognosis in a variety of cancer types. The 3-dimensional protein structure of YB-1 has yet to be determined and its role in transcriptional regulation remains elusive. Drug targeting of transcription factors is often thought to be difficult and there are very few published high-throughput screening approaches.

A Predictor of Early Disease Recurrence in Patients With Breast Cancer Using a Cell-free RNA and Protein Liquid Biopsy.

Introduction: Circulating biomarkers have been increasingly used in the clinical management of breast cancer. The present study evaluated whether RNAs and a protein present in the plasma of patients with breast cancer might have utility as prognostic biomarkers complementary to existing clinical tests.

Patients And Methods: We performed microarray profiling of small noncoding RNAs in plasma samples from 30 patients with breast cancer and 10 control individuals.

Regulation of the interferon-gamma (IFN-γ) pathway by p63 and Δ133p53 isoform in different breast cancer subtypes.

The family consists of three sets of transcription factor genes, , and , each of which expresses multiple RNA variants and protein isoforms. Of these, is mutated in 25-30% of breast cancers. How mutations affect the interaction of family members and their isoforms in breast cancer is unknown.

Gene expression profiling of breast tumours from New Zealand patients.

Aims: New Zealand has one of the highest rates of breast cancer incidence in the world. We investigated the gene expression profiles of breast tumours from New Zealand patients, compared them to gene expression profiles of international breast cancer cohorts and identified any associations between altered gene expression and the clinicopathological features of the tumours.

Methods: Affymetrix microarrays were used to measure the gene expression profiles of 106 breast tumours from New Zealand patients.

Development of biodegradable PLGA nanoparticles surface engineered with hyaluronic acid for targeted delivery of paclitaxel to triple negative breast cancer cells.

This study aimed at development of poly (lactic-co-glycolic acid) (PLGA) nanoparticles embedded with paclitaxel and coated with hyaluronic acid (HA-PTX-PLGA) to actively target the drug to a triple negative breast cancer cells. Nanoparticles were successfully fabricated using a modified oil-in-water emulsion method. The effect of various formulations parameters on the physicochemical properties of the nanoparticles was investigated.

A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology.

TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression.

Multimodal Assessment of Estrogen Receptor mRNA Profiles to Quantify Estrogen Pathway Activity in Breast Tumors.

Background: Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients.

A novel EGR-1 dependent mechanism for YB-1 modulation of paclitaxel response in a triple negative breast cancer cell line.

Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required.

Nanoparticle therapeutics: Technologies and methods for overcoming cancer.

It is anticipated that by 2030 approximately 13 million people will die of cancer. Common cancer therapy often fails due to the development of multidrug resistance (MDR), resulting in high morbidity and poor patient prognosis. Nanotechnology seeks to use drug delivery vehicles of 1-100 nm in diameter, made up of several different materials to deliver anti-cancer drugs selectively to cancer cells and potentially overcome MDR.

Nanoparticulate carriers: an emerging tool for breast cancer therapy.

Breast cancer is a leading cause of death for women in the world. Cancer has the potential to spread to different organs around the body, and form metastases that can even develop after surgical removal of the primary tumour. Nanotechnology offers new promising strategies for the treatment of breast cancer, and has emerged as a powerful tool for fighting cancer.

N-methyl-D-aspartate receptors amplify activation and aggregation of human platelets.

Background: Glutamate is stored in platelet dense granules and large amounts (>400 μM) are released during thrombus formation. N-methyl-d-aspartate glutamate receptors (NMDARs) have been shown in platelets but their roles are unclear.

Materials And Methods: Platelet activation indices (CD62P expression and PAC-1 binding) and platelet aggregation were tested in the presence of well-characterized agonists (glutamate, NMDA, glycine) and antagonists (MK-801, memantine, AP5) of neuronal NMDARs.

Links between the oncoprotein YB-1 and small non-coding RNAs in breast cancer.

Background: The nucleic acid-binding protein YB-1, a member of the cold-shock domain protein family, has been implicated in the progression of breast cancer and is associated with poor patient survival. YB-1 has sequence similarity to LIN28, another cold-shock protein family member, which has a role in the regulation of small noncoding RNAs (sncRNAs) including microRNAs (miRNAs). Therefore, to investigate whether there is an association between YB-1 and sncRNAs in breast cancer, we investigated whether sncRNAs were bound by YB-1 in two breast cancer cell lines (luminal A-like and basal cell-like), and whether the abundance of sncRNAs and mRNAs changed in response to experimental reduction of YB-1 expression.

YB-1: oncoprotein, prognostic marker and therapeutic target?

Hanahan and Weinberg have proposed the 'hallmarks of cancer' to cover the biological changes required for the development and persistence of tumours [Hanahan and Weinberg (2011) Cell 144, 646-674]. We have noted that many of these cancer hallmarks are facilitated by the multifunctional protein YB-1 (Y-box-binding protein 1). In the present review we evaluate the literature and show how YB-1 modulates/regulates cellular signalling pathways within each of these hallmarks.

Targeting p90 ribosomal S6 kinase eliminates tumor-initiating cells by inactivating Y-box binding protein-1 in triple-negative breast cancers.

Y-box binding protein-1 (YB-1) is the first reported oncogenic transcription factor to induce the tumor-initiating cell (TIC) surface marker CD44 in triple-negative breast cancer (TNBC) cells. In order for CD44 to be induced, YB-1 must be phosphorylated at S102 by p90 ribosomal S6 kinase (RSK). We therefore questioned whether RSK might be a tractable molecular target to eliminate TICs.

YB-1, the E2F pathway, and regulation of tumor cell growth.

Background: Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear.

Methods: YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis-free survival using data from 375 of those patients who did not receive adjuvant therapy.

Prognostic association of YB-1 expression in breast cancers: a matter of antibody.

The literature concerning the subcellular location of Y-box binding protein 1 (YB-1), its abundance in normal and cancer tissues, and its prognostic significance is replete with inconsistencies. An explanation for this could be due in part to the use of different antibodies in immunohistochemical and immunofluorescent labeling of cells and tissues. The inconsistencies could also be due to poor resolution of immunohistochemical data.

The importance of RT-qPCR primer design for the detection of siRNA-mediated mRNA silencing.

Background: The use of RNAi to analyse gene function in vitro is now widely applied in biological research. However, several difficulties are associated with its use in vivo, mainly relating to inefficient delivery and non-specific effects of short RNA duplexes in animal models. The latter can lead to false positive results when real-time RT-qPCR alone is used to measure target mRNA knockdown.