Epigenome-wide SRC-1 mediated gene silencing represses cellular differentiation in advanced breast cancer

Abstract Purpose: Despite the clinical utility of endocrine therapies for estrogen receptor–positive (ER) breast cancer, up to 40% of patients eventually develop resistance, leading to disease progression. The molecular determinants that drive this adaptation to treatment remain poorly understood. Methylome aberrations drive cancer growth yet the functional role and mechanism of these epimutations in drug resistance are poorly elucidated. Experimental Design: Genome-wide multi-omics sequencing approach identified a differentially methylated hub of prodifferentiation genes in endocrine resistant breast cancer patients and cell models. Clinical relevance of the functionally validated methyl-targets was assessed in a cohort of endocrine-treated human breast cancers and patient-derived ex vivo metastatic tumors. Results: Enhanced global hypermethylation was observed in endocrine treatment resistant cells and patient metastasis relative to sensitive parent cells and matched primary breast tumor, respectively. Using paired methylation and transcriptional profiles, we found that SRC-1–dependent alterations in endocrine resistance lead to aberrant hypermethylation that resulted in reduced expression of a set of differentiation genes. Analysis of ER-positive endocrine-treated human breast tumors (n = 669) demonstrated that low expression of this prodifferentiation gene set significantly associated with poor clinical outcome (P = 0.00009). We demonstrate that the reactivation of these genes in vitro and ex vivo reverses the aggressive phenotype. Conclusions: Our work demonstrates that SRC-1-dependent epigenetic remodeling is a ’high level’ regulator of the poorly differentiated state in ER-positive breast cancer. Collectively these data revealed an epigenetic reprograming pathway, whereby concerted differential DNA methylation is potentiated by SRC-1 in the endocrine resistant setting. Clin Cancer Res; 24(15); 3692–703. ©2018 AACR.</jats:p

Humanitarian intervention and the genocide in Rwanda

SIGLEGBUnited Kingdo

STEM literacy or literacies? Examining the empirical basis of these constructs

The term ‘STEM literacy’, while often used as a slogan for the goal of STEM education, is open to multiple interpretations and used without much research evidence to support its validity. The purpose of this paper is to review the research literature in science, technology/engineering and mathematics education to examine how literacy in each respective discipline has been defined, conceptualised and studied. The literacies across the disciplines are then compared to identify similarities and differences in order to determine on what basis these literacies can be conceptualised collectively, or not. Based on the similarities found in several language and thought processes of the disciplines, we conclude that there is presently a research basis for postulating a unitary STEM literacy that reflects the shared general capabilities required in all the STEM disciplines. At the same time, there are also substantial differences that support the retention of the existing literacy constructs (i.e., S.T.E.M. literacies) to reflect the specific linguistic, cognitive and epistemic requirements found in each disciplinary area. This distinction from the singular STEM literacy is necessary to highlight the skills and practices that are unique to each particular discipline, and therefore not applicable in all the other disciplines. Given the haphazard rhetoric regarding STEM education, what STEM literacy comprises requires analysis and clear articulation that is framed by literacy research and scholarship in each STEM discipline