Focal adhesion kinase contributes to proliferative potential of ErbB2 mammary tumour cells but is dispensable for ErbB2 mammary tumour induction in vivo

INTRODUCTION: Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer. METHODS: To directly evaluate the role of FAK in mammary tumour progression, we have used a conditional FAK mouse model and mouse mammary tumour virus (MMTV)-driven Cre recombinase strain to inactivate FAK in the mammary epithelium of a transgenic mouse model of ErbB2 breast cancer. RESULTS: Although mammary epithelial disruption of FAK in this model resulted in both a delay in onset and a decrease in the number of neoplastic lesions, mammary tumours occurred in 100% of virgin female mice. All of the tumours and derived metastases that developed were proficient for FAK due to the absence of Cre recombinase expression. The hyperplastic epithelia where Cre-mediated recombination of FAK could be detected exhibited a profound proliferative defect. Consistent with these observations, disruption of FAK in established tumour cells resulted in reduced tumour growth that was associated with impaired proliferation. To avoid the selection for FAK-proficient ErbB2 tumour epithelia through escape of Cre-mediated recombination, we next intercrossed the FAK conditional mice with a separate MMTV-driven ErbB2 strain that co-expressed ErbB2 and Cre recombinase on the same transcriptional unit. CONCLUSIONS: While a delay in tumour induction was noted, FAK-deficient tumours arose in 100% of female animals indicating that FAK is dispensable for ErbB2 tumour initiation. In addition, the FAK-null ErbB2 tumours retained their metastatic potential. We further demonstrated that the FAK-related Pyk2 kinase is still expressed in these tumours and is associated with its downstream regulator p130Cas. These observations indicate that Pyk2 can functionally substitute for FAK in ErbB2 mammary tumour progression

The VicGeneration study - a birth cohort to examine the environmental, behavioural and biological predictors of early childhood caries: background, aims and methods

Background Dental caries (decay) during childhood is largely preventable however it remains a significant and costly public health concern, identified as the most prevalent chronic disease of childhood. Caries in children aged less than five years (early childhood caries) is a rapid and progressive disease that can be painful and debilitating, and significantly increases the likelihood of poor child growth, development and social outcomes. Early childhood caries may also result in a substantial social burden on families and significant costs to the public health system. A disproportionate burden of disease is also experienced by disadvantaged populations. Methods/Design This study involves the establishment of a birth cohort in disadvantaged communities in Victoria, Australia. Children will be followed for at least 18 months and the data gathered will explore longitudinal relationships and generate new evidence on the natural history of early childhood caries, the prevalence of the disease and relative contributions of risk and protective biological, environmental and behavioural factors. Specifically, the study aims to: 1. Describe the natural history of early childhood caries (at ages 1, 6, 12 and 18 months), tracking pathways from early bacterial colonisation, through non-cavitated enamel white spot lesions to cavitated lesions extending into dentine. 2. Enumerate oral bacterial species in the saliva of infants and their primary care giver. 3. Identify the strength of concurrent associations between early childhood caries and putative risk and protective factors, including biological (eg microbiota, saliva), environmental (fluoride exposure) and socio-behavioural factors (proximal factors such as: feeding practices and oral hygiene; and distal factors such as parental health behaviours, physical health, coping and broader socio-economic conditions). 4. Quantify the longitudinal relationships between these factors and the development and progression of early childhood caries from age 1-18 months. Discussion There is currently a lack of research describing the natural history of early childhood caries in very young children, or exploring the interactions between risk and protective factors that extend to include contemporary measures of socio-behavioural factors. This study will generate knowledge about pathways, prevalence and preventive opportunities for early childhood caries, the most prevalent child health inequality

Allometry of the Duration of Flight Feather Molt in Birds

Replacement of flight feathers takes disproportionately more time for large birds than it does for small birds, because feather length increases with body size almost twice as fast as feather growth rate increases

No evidence for a saccadic range effect for visually guided and memory-guided saccades in simple saccade-targeting tasks

International audienceSaccades to single targets in peripheral vision are typically characterized by an undershoot bias. Putting this bias to a test, Kapoula [1] used a paradigm in which observers were presented with two different sets of target eccentricities that partially overlapped each other. Her data were suggestive of a saccadic range effect (SRE): There was a tendency for saccades to overshoot close targets and undershoot far targets in a block, suggesting that there was a response bias towards the center of eccentricities in a given block. Our Experiment 1 was a close replication of the original study by Kapoula [1]. In addition, we tested whether the SRE is sensitive to top-down requirements associated with the task, and we also varied the target presentation duration. In Experiments 1 and 2, we expected to replicate the SRE for a visual discrimination task. The simple visual saccade-targeting task in Experiment 3, entailing minimal top-down influence, was expected to elicit a weaker SRE. Voluntary saccades to remembered target locations in Experiment 3 were expected to elicit the strongest SRE. Contrary to these predictions, we did not observe a SRE in any of the tasks. Our findings complement the results reported by Gillen et al. [2] who failed to find the effect in a saccade-targeting task with a very brief target presentation. Together, these results suggest that unlike arm movements, saccadic eye movements are not biased towards making saccades of a constant, optimal amplitude for the task

Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells

International audienceAcquired resistance to endocrine therapy in breast cancer is a major clinical problem. Previous reports have demonstrated that cell models of acquired endocrine resistance have altered cell–matrix adhesion and a highly migratory phenotype, features which may impact on tumour spread in vivo. Focal adhesion kinase (FAK) is an intracellular kinase that regulates signalling pathways central to cell adhesion, migration and survival and its expression is frequently deregulated in breast cancer. In this study, we have used the novel FAK inhibitor PF573228 to address the role of FAK in the development of endocrine resistance. Whilst total-FAK expression was similar between endocrine-sensitive and endocrine-resistant MCF7 cells, FAK phosphorylation status (Y397 or Y861) was altered in resistance. PF573228 promoted a dose-dependent inhibition of FAK phosphorylation at Y397 but did not affect other FAK activation sites (pY407, pY576 and pY861). Endocrine-resistant cells were more sensitive to these inhibitory effects versus MCF7 (mean IC for FAK pY397 inhibition: 0.43 μM, 0.05 μM and 0.13 μM for MCF7, TamR and FasR cells, respectively). Inhibition of FAK pY397 was associated with a reduction in TamR and FasR adhesion to, and migration over, matrix components. PF573228 as a single agent (0–1 μM) did not affect the growth of MCF7 cells or their endocrine-resistant counterparts. However, treatment of endocrine-sensitive cells with PF573228 and tamoxifen combined resulted in greater suppression of proliferation versus single agent treatment. Together these data suggest the importance of FAK in the process of endocrine resistance, particularly in the development of an aggressive, migratory cell phenotype and demonstrate the potential to improve endocrine response through combination treatment