Socioeconomic inequalities in breast cancer survival in Reunion Island: The contribution of stage at diagnosis as a mediator

IntroductionAlthough breast cancer survival has improved in France, it appears that women living in deprived areas are more likely to die from breast cancer. However, no study has yet examined socioeconomic inequalities in breast cancer survival in La Réunion. Our objective was to examine whether socioeconomic inequalities in breast cancer survival exist in Reunion Island and whether stage at diagnosis could partly explain these differences.MethodsA population-based cohort study of all women on Reunion Island with primary breast cancer diagnosed between 2008 and 2016 was conducted. Each woman was assigned a deprivation index based on her area of residence at diagnosis. Net survival by deprivation group and stage at diagnosis was estimated by the non parametric Pohar Perme method. The role of stage (indirect effect) was assessed using a mediation analysis extended to the relative survival framework.ResultsAt five years, net survival was significantly lower in women living in the most deprived areas than in women living in the least deprived areas (81 % (95 % CI 77–86) and 91 % (95 % CI 89–94), respectively, p < 0.0001), and mediation analysis showed that the contribution of stage at diagnosis to these survival differences was 43 %.DiscussionOur result shows that although measures to promote earlier diagnosis are important, they would only reduce socioeconomic inequalities in breast cancer survival by 43 %. To further investigate these inequalities, future research should explore the role of unmeasured mediators, such as comorbidities and treatment received, as well as the impact of specific interventions that might address the differences in mediator distribution.     

The Wnt/Planar Cell Polarity Protein-tyrosine Kinase-7 (PTK7) Is a Highly Efficient Proteolytic Target of Membrane Type-1 Matrix Metalloproteinase: IMPLICATIONS IN CANCER AND EMBRYOGENESIS*

PTK7 is an essential component of the Wnt/planar cell polarity (PCP) pathway. We provide evidence that the Wnt/PCP pathway converges with pericellular proteolysis in both normal development and cancer. Here, we demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP), a key proinvasive proteinase, functions as a principal sheddase of PTK7. MT1-MMP directly cleaves the exposed PKP⁶²¹↓LI sequence of the seventh Ig-like domain of the full-length membrane PTK7 and generates, as a result, an N-terminal, soluble PTK7 fragment (sPTK7). The enforced expression of membrane PTK7 in cancer cells leads to the actin cytoskeleton reorganization and the inhibition of cell invasion. MT1-MMP silencing and the analysis of the uncleavable L622D PTK7 mutant confirm the significance of MT1-MMP proteolysis of PTK7 in cell functions. Our data also demonstrate that a fine balance between the metalloproteinase activity and PTK7 levels is required for normal development of zebrafish (Danio rerio). Aberration of this balance by the proteinase inhibition or PTK7 silencing results in the PCP-dependent convergent extension defects in the zebrafish. Overall, our data suggest that the MT1-MMP-PTK7 axis plays an important role in both cancer cell invasion and normal embryogenesis in vertebrates. Further insight into these novel mechanisms may promote understanding of directional cell motility and lead to the identification of therapeutics to treat PCP-related developmental disorders and malignancy.     

糖尿病对乳腺癌患者预后影响的Meta 分析

目的：评价中国地区糖尿病对乳腺癌患者预后的影响，为临床工作提供依据。方法：检索万方、中国知网、维普、Medline、 Pubmed、Embase数据库有关糖尿病对乳腺癌患者预后影响的文章，收集数据，进行meta 分析，以合并OR 值作为效应指标。结果： meta 分析共纳入11 篇文献，总共有28589 个病例；合并糖尿病对乳腺癌患者5 年无病生存率有影响[OR=2.48，95%CI （1.81~3.40）；I2=0%，P(Q)=0.42]；合并糖尿病对乳腺癌患者5 年总生存率有影响[OR=2.40，95%CI（1.75~3.29）；I2=81.67%，P(Q)<0. 01]。结论：糖尿病对乳腺癌患者预后有影响，造成生存率降低。     

Flavone-based natural product agents as new lysine-specific demethylase 1 inhibitors exhibiting cytotoxicity against breast cancer cells in vitro

Lysine-specific demethylase 1 (LSD1) has recently emerged as a therapeutic target for cancer. However, almost all LSD1 inhibitors developed to date are chemo-synthesised molecules. In this study, the LSD1 inhibitory activity of 12 natural flavones, including four aglycones and their corresponding monoglycosides and diglucosides, was evaluated. Based on the structure–activity relationships, LSD1 inhibition activity was greater for flavonoid monoglycosides than their aglycones lacking the sugar moiety. The effects of isoquercitrin, which exhibited optimal LSD1 inhibitory activity, on cancer cell properties were evaluated. Isoquercitrin induced the expression of key proteins in the mitochondrial-mediated apoptosis pathway and caused apoptosis in LSD1-overexpressing MDA-MB-231 cells via the inhibition of LSD1. These findings suggest that natural LSD1 inhibitors, and particularly isoquercitrin, are promising for cancer treatment.     

Associations of iron status with breast cancer risk factors in adult women: Findings from National Health and Nutrition Examination Survey 2017–2018

ObjectiveThis study examined the association between iron status and a set of breast cancer risk factors among U.S. adult women aged 20–80 years.MethodsData from National Health and Nutrition Examination Survey (2017–2018) were used to examine the relation between serum ferritin, serum iron and transferrin saturation with a set of breast cancer risk factors [body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), fasting plasma glucose, insulin and HOMA-IR]. The multivariable linear regressions were used controlling for age, race/ethnicity, menopause status, education level, smoking status, alcohol consumption, physical activity, high-sensitivity C-reactive protein (hsCRP) and total energy intake.ResultsHbA1c, BMI and waist circumference data were available for 1902 women with a fasting sample (n = 913) for fasting plasma glucose, insulin and HOMA-IR. Transferrin saturation had significant, inverse associations with BMI, waist circumference and HbA1c. The size of difference observed were that participants in the fourth quartile of transferrin saturation had a 4.50 kg/m² smaller BMI, a 9.36 cm smaller waist circumference and a 0.1 % lower HbA1c level than participants in the first quartile. Similarly, serum iron concentrations were inversely associated with BMI and waist circumference. In addition, serum iron had significant, inverse associations with insulin and HOMA-IR. Sensitivity analyses among men gave similar results. For serum ferritin, there was a trend towards a positive association between waist circumference, HbA1c and fasting plasma glucose with serum ferritin. However, the associations did not reach statistical significance among women.ConclusionsIron status may impact breast cancer risk via effects on adiposity or glucose metabolism. The findings should be confirmed with further prospective data.     

Detection of cyclin D1 mRNA by hybridization sensitive NIC–oligonucleotide probe

A large group of fluorescent hybridization probes, includes intercalating dyes for example thiazole orange (TO). Usually TO is coupled to nucleic acids post-synthetically which severely limits its use. Here, we have developed a phosphoramidite monomer, 10, and prepared a 2′-OMe-RNA probe, labeled with 5-(trans-N-hexen-1-yl-)-TO-2′-deoxy-uridine nucleoside, dU^TO, (Nucleoside bearing an Inter-Calating moiety, NIC), for selective mRNA detection. We investigated a series of 15-mer 2′-OMe-RNA probes, targeting the cyclin D1 mRNA, containing one or several dU^TO at various positions. dU^TO-2′-OMe-RNA exhibited up to 7-fold enhancement of TO emission intensity upon hybridization with the complementary RNA versus that of the oligomer alone. This NIC-probe was applied for the specific detection of a very small amount of a breast cancer marker, cyclin D1 mRNA, in total RNA extract from cancerous cells (250 ng/μl). Furthermore, this NIC-probe was found to be superior to our related NIF (Nucleoside with Intrinsic Fluorescence)-probe which could detect cyclin D1 mRNA target only at high concentrations (1840 ng/μl). Additionally, dU^T can be used as a monomer in solid-phase oligonucleotide synthesis, thus avoiding the need for post-synthetic modification of oligonucleotide probes. Hence, we propose dU^TO oligonucleotides, as hybridization probes for the detection of specific RNA in homogeneous solutions and for the diagnosis of breast cancer.     

Contacting the brain – aspects of a technology assessment of neural implants

The public interest in neural implants has grown considerably in recent years. Progress within related research areas in combination with increasing – albeit overly optimistic and indiscriminate – mass media coverage have led to the impression that the possibilities of neural prosthetics have grown enormously. But a closer look reveals that the reasons for the intensified interest are varied and cannot be attributed to technical progress alone. Some neural prostheses that have been under development for many years have not left the clinical development phase despite intensive research activities. Other implants, like cardiac pacemakers and cochlea implants, are mature products that have already been implanted in a large number of patients. From the public perspective and in media reports, progress in the development of neural implants is associated with new achievements in other fields of neuroscience. Communications on new applications of functional magnetic resonance imaging (fMRI) may suggest that a number of cognitive functions are now easily accessible with technological means. The fact that the interpretation of the results of fMRI studies depends on many conditions and is partly disputed also within the scientific community has been discussed in many publications but only very limited, in the general media. Besides this, research results and implementations in the area of electroencephalography and magnetoencephalography have sparked further debate on the question of free will, on determinism and indeterminism, and have attracted a large media response. The purpose of this paper is to discuss some societal and ethical aspects of neural implants from a technology assessment perspective. Technology assessment (TA) aims at providing knowledge about impacts and consequences of (new) technologies as well as about political and societal ways of dealing with them. It reflects about implementation conditions of technology and potential technology conflicts. Over the last years, neural implants became a subject for TA since they have gained a higher attention in both the political arena and the general public. Especially the ethical and social implications of technologies that electrically stimulate the brain and the possibilities of changing personality traits, changing moods, and perhaps enhancing human cognitive capabilities are central issues in related discussions. In this paper, we want to briefly summarize some of the key arguments as well as topics for future discussion and research.     

Therapeutic options for triple-negative breast cancers with defective homologous recombination

Breast cancer is the most common malignancy among women in developed countries, affecting more than a million women per year worldwide. Over the last decades, our increasing understanding of breast cancer biology has led to the development of endocrine agents against hormone receptor-positive tumors and targeted therapeutics against HER2-expressing tumors. However, no targeted therapy is available for patients with triple-negative breast cancer, lacking expression of hormone receptors and HER2. Overlap between BRCA1-mutated breast cancers and triple-negative tumors suggests that an important part of the triple-negative tumors may respond to therapeutics targeting BRCA1-deficient cells. Here, we review the features shared between triple-negative, basal-like and BRCA1-related breast cancers. We also discuss the development of novel therapeutic strategies to target BRCA1-mutated tumors and triple-negative tumors with BRCA1-like features. Finally, we highlight the utility of mouse models for BRCA1-mutated breast cancer to optimize (combination) therapy and to understand drug resistance.     

MicroRNA-216b targets HK2 to potentiate autophagy and apoptosis of breast cancer cells via the mTOR signaling pathway

Patients suffering from breast cancer (BC) still have a poor response to treatments, even though early detection and improved therapy have contributed to a reduced mortality. Recent studies have been inspired on the association between microRNAs (miRs) and therapies of BC. The current study set out to investigate the role of miR-216b in BC, and further analyze the underlining mechanism. Firstly, hexokinase 2 (HK2) and miR-216b were characterized in BC tissues and cells by RT-qPCR and Western blot assay. In addition, the interaction between HK2 and miR-216b was analyzed using dual luciferase reporter assay. BC cells were further transfected with a series of miR-216b mimic or inhibitor, or siRNA targeting HK2, so as to analyze the regulatory mechanism of miR-216b, HK2 and mammalian target of rapamycin (mTOR) signaling pathway, and to further explore their regulation in BC cellular behaviors. The results demonstrated that HK2 was highly expressed and miR-216b was poorly expressed in BC cells and tissues. HK2 was also verified as a target of miR-216b with online databases and dual luciferase reporter assay. Functionally, miR-216b was found to be closely associated with BC progression via inactivating mTOR signaling pathway by targeting HK2. Moreover, cell viability, migration and invasion were reduced as a result of miR-216b upregulation or HK2 silencing, while autophagy, cell cycle arrest and apoptosis were induced. Taken together, our findings indicated that miR-216b down-regulates HK2 to inactivate the mTOR signaling pathway, thus inhibiting the progression of BC. Hence, this study highlighted a novel target for BC treatment.