Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity

The epithelial-to-mesenchymal transition (EMT) is a critical developmental process that has recently come to the forefront of cancer biology. In breast carcinomas, acquisition of a mesenchymal-like phenotype that is reminiscent of an EMT, termed oncogenic EMT, is associated with pro-metastatic properties, including increased motility, invasion, anoikis resistance, immunosuppression and cancer stem cell characteristics. This oncogenic EMT is a consequence of cellular plasticity, which allows for interconversion between epithelial and mesenchymal-like states, and is thought to enable tumor cells not only to escape from the primary tumor, but also to colonize a secondary site. Indeed, the plasticity of cancer cells may explain the range of pro-metastatic traits conferred by oncogenic EMT, such as the recently described link between EMT and cancer stem cells and/or therapeutic resistance. Continued research into this relationship will be critical in developing drugs that block mechanisms of breast cancer progression, ultimately improving patient outcomes

Mouse mammary stem cells express prognostic markers for triple-negative breast cancer

Introduction Triple negative breast cancer (TNBC) is a heterogeneous group of tumours in which chemotherapy, the current mainstay of systemic treatment, is often initially beneficial but with a high risk of relapse and metastasis. There is currently no means of predicting which TNBC will relapse. We tested the hypothesis that the biological properties of normal stem cells are re-activated in tumour metastasis and that, therefore, the activation of normal mammary stem cell-associated gene sets in primary TNBC would be highly prognostic for relapse and metastasis. Methods Mammary basal stem and myoepithelial cells were isolated by flow cytometry and tested in low dose transplant assays. Gene expression microarrays were used to establish expression profiles of the stem and myoepithelial populations; these were compared to each other and to our previously established mammary epithelial gene expression profiles. Stem cell genes were classified by Gene Ontology (GO) analysis and the expression of a subset analysed in the stem cell population at single cell resolution. Activation of stem cell genes was interrogated across different breast cancer cohorts and within specific subtypes and tested for clinical prognostic power. Results A set of 323 genes was identified that was expressed significantly more highly in the purified basal stem cells compared to all other cells of the mammary epithelium. 109 out of 323 genes had been associated with stem cell features in at least one other study in addition to our own, providing further support for their involvement in the biology of this cell type. GO analysis demonstrated an enrichment of these genes for an association with cell migration, cytoskeletal regulation and tissue morphogenesis, consistent with a role in invasion and metastasis. Single cell resolution analysis showed that individual cells co-expressed both epithelial- and mesenchymal-associated genes/proteins. Most strikingly, we demonstrated that strong activity of this stem cell gene set in TNBCs identified those tumours most likely to rapidly progress to metastasis. Conclusions Our findings support the hypothesis that the biological properties of normal stem cells are drivers of metastasis and that these properties can be used to stratify patients with a highly heterogeneous disease such as TNBC

The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

From Springer Nature via Jisc Publications RouterHistory: received 2020-04-21, rev-recd 2021-03-23, accepted 2021-04-14, registration 2021-04-15, pub-electronic 2021-05-12, online 2021-05-12, pub-print 2021-06-10Publication status: PublishedFunder: Worldwide Cancer Research; doi: https://doi.org/10.13039/100011713; Grant(s): 15-1283Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187; Grant(s): MC_PC_18056Abstract: There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior

Seasonal prevalence of bovine fasciolosis and its direct economic losses (del) due to liver condemnation at Makurdi abattoirs north central Nigeria

This study was conducted to report the prevalence of bovine fasciolosis and to estimate the direct  economic losses (DEL) from condemnation of liver as a result of detection of lesions of fasciolosis in cattle slaughtered in Makurdi abattoirs. Retrospective data were collected from the abattoir records obtained  from Ministry of Agriculture and Natural Resources (MANR) Makurdi, from 2008 to 2012. Direct economic losses were calculated based on a pilot study to determine the average price of liver per kilogram  (AvP/kg) and using the formula: DEL = w × AvP/kg, where is the number of livers condemned and is the average liver weight in kg. Between 2008 and 2012, 64,978 cattle were slaughtered at Makurdi abattoirs, out of which 9,478 cattle were infected with Fasciola species. This represents an overall prevalence of 14.56% (95%, C.I.: 12.99 – 16.85%). Annual prevalence of bovine fasciolosis was  significantly (P <0.05) high in 2010 and decreased from 2011 to 2012. During the late dry season, the  prevalence of bovine fasciolosis was significantly high (P <0.05). A total of 4220 liver were condemned  during the study period. This amounted to 12660 kg and valued at ₦12,660,000.00 ($79251.60 USD). The  highest prevalence was recorded during the late dry season. However, cattle acquire the infection during  the wet season and early dry season. Pathological lesions were much obvious during the late dry season  possibly when the animals were most stressed, hence we suggest that control measures should be  targeted towards wet and early dry seasons. Bovine fasciolosis is prevalent in cattle slaughtered in  Makurdi abattoirs and accounts for huge financial losses.Keywords: Bovine fasciolosis, Economic losses, Makurdi, Prevalence, Seaso

Pathological changes associated with an outbreak of colibacillosis in a commercial broiler flock

Escherichia coli infection was diagnosed in 5-week old broiler chickens raised intensively on a medium-sized commercial farm in Gaube-Kuje, Abuja, Nigeria. Signs of weakness, depression and inappetance with ruffled feathers and pasted vents were reportedly observed in affected birds within the flock. Detailed post mortem examinations revealed diffuse splenomegaly and hepatomegaly with multifocal greyish areas on their surfaces while the diffusely enlarged kidneys were congested with mottled pale appearance. Histopathologically, the liver of affected broilers showed diffuse congestion, multifocal coagulative necrosis and cellular infiltration. Generalized perivascular and inter-septal oedema and haemorrhage were observed in the lungs of affected broilers with generalized lymphocytic depletion within the spleen as well as locally extensive congestion and haemorrhage within the kidney, and cellular infiltration and necrosis within heart musculatures. Microbiological evaluation of liver samples yielded pure E. coli growth only. A diagnosis of colibacillosis, especially colisepticaemia, was made with appropriate treatment based on culture and sensitivity test result involving Levofloxacin(R). The client was consequently advised to guard against possible predisposing factors as control and preventive measures for the disease outbreak on the farm.Keywords: Broiler chickens, Colibacillosis, Gross pathology, Histopathology, Natural infectio

Montolío Durán, Estrella (2010), Estrategias de comunicación para mujeres directivas, Barcelona, Departament de Treball de la Generalitat de Cataluya y Fondo social Europeo, pp. 138.

Background Basal-like and triple negative breast cancer (TNBC) share common molecular features, poor prognosis and a propensity for metastasis to the brain. Amplification of epidermal growth factor receptor (EGFR) occurs in ~50% of basal-like breast cancer, and mutations in the epidermal growth factor receptor (EGFR) have been reported in up to ~ 10% of Asian TNBC patients. In non-small cell lung cancer several different mutations in the EGFR tyrosine kinase domain confer sensitivity to receptor tyrosine kinase inhibitors, but the tumourigenic potential of EGFR mutations in breast cells and their potential for targeted therapy is unknown. Materials and Methods Constructs containing wild type, G719S or E746-A750 deletion mutant forms of EGFR were transfected into the MCF10A breast cells and their tumorigenic derivative, MCF10CA1a. The effects of EGFR over-expression and mutation on proliferation, migration, invasion, response to gefitinib, and tumour formation in vivo was investigated. Copy number analysis and whole exome sequencing of the MCF10A and MCF10CA1a cell lines were also performed. Results Mutant EGFR increased MCF10A and MCF10CA1a proliferation and MCF10A gefitinib sensitivity. The EGFR-E746-A750 deletion increased MCF10CA1a cell migration and invasion, and greatly increased MCF10CA1a xenograft tumour formation and growth. Compared to MCF10A cells, MCF10CA1a cells exhibited large regions of gain on chromosomes 3 and 9, deletion on chromosome 7, and mutations in many genes implicated in cancer. Conclusions Mutant EGFR enhances the oncogenic properties of MCF10A cell line, and increases sensitivity to gefitinib. Although the addition of EGFR E746-A750 renders the MCF10CA1a cells more tumourigenic in vivo it is not accompanied by increased gefitinib sensitivity, perhaps due to additional mutations, including the PIK3CA H1047R mutation, that the MCF10CA1a cell line has acquired. Screening TNBC/basal-like breast cancer for EGFR mutations may prove useful for directing therapy but, as in non-small cell lung cancer, accompanying mutations in PIK3CA may confer gefitinib resistance

Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer

Cancer stem cells (CSCs) are responsible for aggressive tumor growth, metastasis and therapy resistance. In this study, we evaluated the effects of Shikonin (Shk) on breast cancer and found its anti-CSC potential. Shk treatment decreased the expression of various epithelial to mesenchymal transition (EMT) and CSC associated markers. Kinase profiling array and western blot analysis indicated that Shk inhibits STAT3, FAK and Src activation. Inhibition of these signaling proteins using standard inhibitors revealed that STAT3 inhibition affected CSCs properties more significantly than FAK or Src inhibition. We observed a significant decrease in cell migration upon FAK and Src inhibition and decrease in invasion upon inhibition of STAT3, FAK and Src. Combined inhibition of STAT3 with Src or FAK reduced the mammosphere formation, migration and invasion more significantly than the individual inhibitions. These observations indicated that the anti-breast cancer properties of Shk are due to its potential to inhibit multiple signaling proteins. Shk also reduced the activation and expression of STAT3, FAK and Src in vivo and reduced tumorigenicity, growth and metastasis of 4T1 cells. Collectively, this study underscores the translational relevance of using a single inhibitor (Shk) for compromising multiple tumor-associated signaling pathways to check cancer metastasis and stem cell load