A SRC-slug-TGFß2 signaling axis drives poor outcomes in triple-negative breast cancers.

BACKGROUND: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance. METHODS: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFß2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models. RESULTS: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFß2-antisense 1 to promote TGFß2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin. CONCLUSION: Targeting the SRC-Slug-TGFß2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.

In our study, we focused on a particular subtype of aggressive breast cancer called Triple-Negative Breast Cancer (TNBC). We investigated a complex series of events that contribute to poor outcomes in this disease and uncovered a crucial signaling cascade driving tumor growth and progression.At the core of this signaling cascade are three key proteins: SRC, AKT, and ERK2. Together, they form a pathway that activates a transcription factor called Slug. Transcription factors act like molecular switches, controlling the expression of genes. Once Slug is activated, it strongly suppresses genes that would normally restrict cell growth and cell spread.One of the genes downregulated by Slug is TGFB2-AS1. This product of the TGFB2-AS1 gene normally controls levels of its target protein called TGF-beta2 (TGFB2), a protein which has roles in cell growth, cell migration and differentiation. Slug downregulation of TGFB2-AS1 results in higher TGFB2 levels, and this in turn contributes to the uncontrolled growth and spread of cancer cells. TGFB2, and other proteins in this pathway (SRC, AKT, ERK2, and a Slug interactor called LSD1) all maintain the stability of Slug, meaning that Slug levels remain high and drive the aggressive features of this subtype of breast cancer.Overall, our research sheds light on the intricate molecular mechanisms driving aggressive TNBC. It also identifies potential targets for future therapies, aimed at disrupting this harmful signaling pathway and potentially improving patient outcomes for this disease.

miR-210 is induced by hypoxia and regulates neural cell adhesion molecule in prostate cells.

Hypoxia in prostate tumours has been associated with disease progression and metastasis. MicroRNAs are short noncoding RNA molecules that are important in several cell processes, but their role in hypoxic signalling is still poorly understood. miR-210 has been linked with hypoxic mechanisms, but this relationship has been poorly characterised in prostate cancer. In this report, the link between hypoxia and miR-210 in prostate cancer cells is investigated. Polymerase chain reaction analysis demonstrates that miR-210 is induced by hypoxia in prostate cancer cells using in vitro cell models and an in vivo prostate tumour xenograft model. Analysis of The Cancer Genome Atlas prostate biopsy datasets shows that miR-210 is significantly correlated with Gleason grade and other clinical markers of prostate cancer progression. Neural cell adhesion molecule (NCAM) is identified as a target of miR-210, providing a biological mechanism whereby hypoxia-induced miR-210 expression can contribute to prostate cancer. This study provides evidence that miR-210 is an important regulator of cell response to hypoxic stress and proposes that its regulation of NCAM may play an important role in the pathogenesis of prostate cancer.

MiR-21 Is Induced by Hypoxia and Down-Regulates RHOB in Prostate Cancer.

Tumour hypoxia is a well-established contributor to prostate cancer progression and is also known to alter the expression of several microRNAs. The over-expression of microRNA-21 (miR-21) has been consistently linked with many cancers, but its role in the hypoxic prostate tumour environment has not been well studied. In this paper, the link between hypoxia and miR-21 in prostate cancer is investigated. A bioinformatic analysis of The Cancer Genome Atlas (TCGA) prostate biopsy datasets shows the up-regulation of miR-21 is significantly associated with prostate cancer and clinical markers of disease progression. This up-regulation of miR-21 expression was shown to be caused by hypoxia in the LNCaP prostate cancer cell line in vitro and in an in vivo prostate tumour xenograft model. A functional enrichment analysis also revealed a significant association of miR-21 and its target genes with processes related to cellular hypoxia. The over-expression of miR-21 increased the migration and colony-forming ability of RWPE-1 normal prostate cells. In vitro and in silico analyses demonstrated that miR-21 down-regulates the tumour suppressor gene Ras Homolog Family Member B (RHOB) in prostate cancer. Further a TCGA analysis illustrated that miR-21 can distinguish between different patient outcomes following therapy. This study presents evidence that hypoxia is a key contributor to the over-expression of miR-21 in prostate tumours, which can subsequently promote prostate cancer progression by suppressing RHOB expression. We propose that miR-21 has good potential as a clinically useful diagnostic and prognostic biomarker of hypoxia and prostate cancer.

Androgen receptor-mediated transcriptional repression targets cell plasticity in prostate cancer.

Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve-advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq datasets and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity and that this repressive function could be pathologically abrogated by AR variants in PCa.

Appetite-regulating hormones-leptin, adiponectin and ghrelin-and the development of prostate cancer: a systematic review and exploratory meta-analysis.

BACKGROUND: Obesity has been proposed as a risk factor for prostate cancer (PCa). In obesity, serum levels of the appetite-regulating hormones-leptin, adiponectin, and ghrelin-become deregulated. OBJECTIVE: To explore whether serum levels of appetite-regulating hormones associate with the incidence of PCa, the incidence of advanced disease, or PCa-specific mortality. METHODS: PRISMA guidelines were followed. A systematic search for relevant articles published until March 2019 was performed using the databases PubMed, EMBASE, and Web of Science. Observational studies with data on serum levels of leptin, adiponectin, or ghrelin and PCa outcome were included. Meta-analysis was used to combine risk estimates. Meta-relative risks (mRRs) were calculated using random effects models. When available, raw data was pooled. Publication bias was assessed by funnel plot and Begg's test. RESULTS: Thirty-five studies were eligible for inclusion. The qualitative analysis indicated that leptin was not consistently associated with any PCa outcome, although several cohorts reported decreased adiponectin levels in men who later developed advanced PCa. Based on the meta-analysis, there was no significant effect of leptin on PCa incidence (mRR = 0.93 (95% CI 0.75-1.16), p = 0.52) or advanced PCa (mRR = 0.90 (95% CI 0.74-1.10), p = 0.30). There were insufficient studies to estimate the mRR of PCa incidence for men with the highest levels of adiponectin. The combined risk of advanced PCa for men with the highest levels of adiponectin was reduced but did not reach significance (mRR = 0.81 (95% CI 0.61-1.08), p = 0.15). CONCLUSIONS: The current evidence does not suggest an association between leptin and PCa outcome. However, there may be an inverse association between adiponectin and the incidence of advanced PCa that should be investigated by further studies. Serum ghrelin has not been largely investigated.