Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models.

BACKGROUND: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear. METHODS: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays. RESULTS: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab. CONCLUSION: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies.

Immunohistochemical expression of apolipoprotein B and 4-hydroxynonenal proteins in colorectal carcinoma patients: a retrospective study.

AIM: To assess the association of the expression of apolipoprotein B (apoB) and 4-hydroxynonenal (4HNE) with the clinicopathological data of patients with colorectal cancer (CRC). METHODS: We obtained 80 CRC histopathological specimens sent to the Pathology Laboratory of Hospital Universiti Sains Malaysia from 2015 to 2019. Data on demographic factors, body mass index (BMI), and clinicopathological characteristics were also collected. Formalin-fixed paraffin-embedded tissues were stained by using an optimized immunohistochemical protocol. RESULTS: Patients were mostly older than 50 years, male, Malay, and overweight or obese. A high apoB expression was observed in 87.5% CRC samples (70/80), while a high 4HNE expression was observed in only 17.5% (14/80) of CRCs. The expression of apoB was significantly associated with the sigmoid and rectosigmoid tumor sites (p =0.001) and tumor size 3-5 cm (p =0.005). 4HNE expression was significantly associated with tumor size 3-5 cm (p =0.045). Other variables were not significantly associated with the expression of either marker. CONCLUSION: ApoB and 4HNE proteins may play a role in promoting CRC carcinogenesis.

Unraveling Roles of miR-27b-3p as a Potential Biomarker for Breast Cancer in Malay Women via Bioinformatics Analysis.

Abnormal miRNA expression has been associated with breast cancer. Knowing miRNA and its target genes gives a better understanding of the biological mechanism behind the development of breast cancer. Here, we evaluated the potential prognostic and predictive values of miRNAs in breast cancer development by analyzing Malay women with breast cancer expression profiles. Seven differentially expressed miRNAs (DEMs) were subjected to miRNA‒target interaction network analysis (MTIN). A comprehensive MTIN was developed by integrating the information on miRNA and target gene interactions from five independent databases, including DIANA-TarBase, miRTarBase, miRNet, miRDB, and DIANA-microT. To understand the role of miRNAs in the progress of breast cancer, functional enrichment analysis of the miRNA target genes was conducted, followed by survival analysis to assess the prognostic values of the miRNAs and their target genes. In total, 1416 interactions were discovered among seven DEMs and 1274 target genes with a confidence score (CS) > 0.8. The overall survival analysis of the three most DEMs revealed a significant association of miR-27b-3p with poor prognosis in the TCGA breast cancer patient cohort. Further functional analysis of 606 miR-27b-3p target genes revealed their involvement in cancer-related processes and pathways, including the progesterone receptor signaling pathway, PI3K-Akt pathway, and EGFR transactivation. Notably, six high-confidence target genes (BTG2, DNAJC13, GRB2, GSK3B, KRAS, and UBR5) were discovered to be associated with worse overall survival in breast cancer patients, underscoring their essential roles in breast cancer development. Thus, we suggest that miR-27b-3p has significant potential as a biomarker for detecting breast cancer and can provide valuable understanding regarding the molecular mechanisms of the disease.

nNav1.5 expression is associated with glutamate level in breast cancer cells

Abstract Background: Glutamate and voltage-gated sodium channels, both have been the target of intense investigation for its involvement in carcinogenesis and progression of malignant disease. Breast cancer with increased level of glutamate often metastasize to other organs (especially bone), whilst re-expression of 'neonatal' Nav1.5, nNav1.5 in breast cancer is known to promote cell invasion in vitro, metastasis in vivo and positive lymph node metastasis in patients. Methods: In this study, the role of nNav1.5 in regulating glutamate level in human breast cancer cells was examined using pharmacological approach (VGSCs specific blocker, TTX, glutamate release inhibitor, riluzole and siRNA-nNav1.5). Effect of these agents were evaluated based on endogenous and exogenous glutamate concentration using glutamate fluorometric assay, mRNA expression of nNav1.5 using qPCR and finally, invasion using 3D culture assay. Results: Endogenous and exogenous glutamate levels were significantly higher in aggressive human breast cancer cells, MDA-MB-231 cells compared to less aggressive human breast cancer cells, MCF-7 and non-cancerous human breast epithelial cells, MCF-10A. Treatment with TTX to MDA-MB-231 cells resulted in significant reduction of endogenous and exogenous glutamate levels corresponded with significant suppression of cell invasion. Subsequently, downregulation of nNav1.5 gene was observed in TTX-treated cells. Conclusions: An interesting link between nNav1.5 expression and glutamate level in aggressive breast cancer cells was detected and requires further investigation.

Andrographolide is an Alternative Treatment to Overcome Resistance in ER-Positive Breast Cancer via Cholesterol Biosynthesis Pathway.

Oestrogen receptor (ER)-positive breast cancer is one of the common forms of breast cancer affecting women worldwide. ER-positive breast cancer patients are subjected to anti-oestrogen therapy such as selective oestrogen receptor modulator (SERM) and aromatase inhibitors (AIs). Recently, the emergence of resistance to anti-oestrogen treatment is under intensive focus. The different mechanisms postulated to explain the occurrence of resistance in ER-positive breast cancer treatment include the loss of ER function and the crosstalk between signalling pathways in cancer cells. Recent literature highlighted that the cholesterol biosynthesis pathway acts as a novel mechanism underlying resistance to oestrogen deprivation. The present study aimed to highlight the role of cholesterol biosynthesis in anti-oestrogen treatment resistance, putatively suggesting an alternative plant-based treatment using andrographolide from Andrographis paniculata. The hypolipidaemic effect of andrographolide can be utilised to prevent the resistance in the treatment of ER-positive breast cancer contributed by cholesterol biosynthesis.

Overexpression of DNA methyltransferase 1 (DNMT1) protein in astrocytic tumour and its correlation with O6-methylguanine-DNA methyltransferase (MGMT) expression.

BACKGROUND: The relationship between DNA methyltransferase (DNMT) and O6-methylguanine-DNA methyltransferase (MGMT) in mediating tumorigenesis is still poorly understood. This study was carried out to investigate a correlation between DNMT1 and MGMT immunoexpression in astrocytic tumour samples. METHODS: Formalin-fixed paraffin embedded tissues of astrocytic tumour patients was obtained from an observational study conducted in Hospital Universiti Sains Malaysia (USM), which was performed from January 1997 until May 2012. Patient's histological information was retrieved from the accessible Pathology Registry. Immunohistochemistry (IHC) staining was performed to assess DNMT1 and MGMT expressions in patients' tumours. RESULTS: Our data showed that DNMT1 was highly expressed in high grade astrocytic tumours. A multiple regression analysis demonstrated a significant association of DNMT1 overexpression with tumour grade III and IV (GIII: OR=5.802; 95% CI: 1.059, 31.785; p value=0.043; GIV: OR=40.663; 95% CI=4.069, 406.347; p value=0.002). The MGMT protein was downregulated in tumours with higher grade as evident by a reduction mean H-score for MGMT expression from GI to GIV [28.36 ± 43.88, 28.08 ± 33.67, 26.00 ± 48.70 and 16.20 ± 35.61]. However, a good negative correlation was observed between DNMT1 and MGMT in high grade tumour [Spearman correlation test: r=-0.561, p value ≤ 0.001 in percentage expression and r=-0.576, p value ≤ 0.001 in H score]. CONCLUSION: DNMT1 overexpression was seen correlated with a reduction of MGMT protein expression in high grade astrocytic tumour. Understanding the role of these markers could be important to overcome astrocytic tumour aggresiveness.