TBX2 acts as a potent transcriptional silencer of tumour suppressor genes through interaction with the CoREST complex to sustain the proliferation of breast cancers.

Chromosome 17q23 amplification occurs in 20% of primary breast tumours and is associated with poor outcome. The TBX2 gene is located on 17q23 and is often over-expressed in this breast tumour subset. TBX2 is an anti-senescence gene, promoting cell growth and survival through repression of Tumour Suppressor Genes (TSGs), such as NDRG1 and CST6. Previously we found that TBX2 cooperates with the PRC2 complex to repress several TSGs, and that PRC2 inhibition restored NDRG1 expression to impede cellular proliferation. Here, we now identify CoREST proteins, LSD1 and ZNF217, as novel interactors of TBX2. Genetic or pharmacological targeting of CoREST emulated TBX2 loss, inducing NDRG1 expression and abolishing breast cancer growth in vitro and in vivo. Furthermore, we uncover that TBX2/CoREST targeting of NDRG1 is achieved by recruitment of TBX2 to the NDRG1 promoter by Sp1, the abolishment of which resulted in NDRG1 upregulation and diminished cancer cell proliferation. Through ChIP-seq we reveal that 30% of TBX2-bound promoters are shared with ZNF217 and identify novel targets repressed by TBX2/CoREST; of these targets a lncRNA, LINC00111, behaves as a negative regulator of cell proliferation. Overall, these data indicate that inhibition of CoREST proteins represents a promising therapeutic intervention for TBX2-addicted breast tumours.

Examining Mid-Upper Arm Circumference Malnutrition z-Score Thresholds.

BACKGROUND: Anthropometric z-scores used commonly for diagnosis and determining degree of malnutrition, specifically body mass index (BMIz), weight-for-length (WLz), and mid-upper arm circumference (MUACz), are not wholly concordant, yet the proposed thresholds for classification are identical. This study was designed to critically examine MUACz thresholds and their ability to correctly classify nutrition status. METHODS: This was a 2-year, prospective single-center study of children ≤18 years seen by registered dietitians within a large pediatric institution. The sensitivity, specificity, and predictive performance of the malnutrition classification thresholds were estimated against clinician-based classification. RESULTS: Sixty-one dietitians enrolled 10,401 patients with distributions of z-scores for weight (-0.5 ± 1.9), length (-0.8 ± 1.6), BMI or WL (-0.1 ± 1.8), and MUAC (-0.4 ± 1.5), suggesting participants were smaller and shorter than the reference U.S. POPULATION: Distributions of MUACz were broad and overlapped between nutrition classification groups, an observation that extended to BMIz and WLz as well. Consequently, existing thresholds do not accurately classify 100% of children. Misclassification rates increase, with increasing severity ranging from 8% in children with no malnutrition to 71% in children with severe malnutrition. Algorithm- and manually-based refinement of thresholds result in mixed improvements and can be explored by the reader with the associated supplement. CONCLUSION: The sensitivity of proposed MUACz thresholds systematically decreases with increasing severity of malnutrition and will require optimization if we aim to limit the number of children at risk of misclassification. Indicators for overnutrition remain to be addressed but are explored herein.