👤 Lawrence Lum

Breast cancer is the leading cause of cancer-related mortality in African American (AA) women. In this study we evaluated the serum proteomic profile of AA women with breast cancer using an integrated proteomic framework with multivariate pattern analysis. Using 2D-DIGE, thousands of serum protein spots were detected across 33 gels; 46 spots met criteria for presence, statistical significance, and differential expression. Proteins from the spots were identified by MALDI-TOF/TOF and matched in curated databases, highlighting serum biomarkers including ceruloplasmin, alpha-2-macroglobulin, complement component C3 and C6, alpha-1-antitrypsin, alpha-1B-glycoprotein, alpha-2-HS-glycoprotein and haptoglobin-related protein. LC-MS/MS analysis revealed 163 differentiating peptides after imputing and filtering 286 peptides. These were evaluated using cumulative distribution function (CDF) analysis, a nonparametric method suited for limited sample sizes. Peptide patterns were explored with Random Forest, showing concordance with CDF. The model achieved an AUC of 0.85 at the peptide level. This workflow identified differentiating proteins (CERU, A2MG, CO3, VTDB, HEMO, APOB, APOA4, CFAH, CO4A, AACT, K1C10, ITIH2, ITIH4), highlighting CERU, A2MG, and CO3 with overexpression and reproducible identification across platforms. We present an integrated, non-invasive serum protein biomarker signature panel specific to AA women, through reproducible proteomic sensor framework to support early detection and breast cancer prevention. Show less

Elevated Lipoprotein(a) [Lp(a)] is a genetic risk factor for cardiovascular diseases affecting 20% of the world's population, with multiple published consensus statements that recommend testing and management strategies. However, elevated Lp(a) remains under-detected and under-treated worldwide. Our qualitative study explored the perspectives of cardiology healthcare professionals regarding the barriers and enablers for Lp(a) detection and management. Guided by Theoretical Domains Framework, we conducted 41 qualitative semi-structured one-on-one interviews in a cardiology department at a high-volume hospital in Singapore from October to December 2023. Healthcare professionals were purposively sampled across role and seniority to include doctors (specialists and interns), specialist nurses and dedicated pharmacists. Through an inductive process, we constructed qualitative codes followed by code-mapping to arrive at higher-order sub-categories, categories, and eventually themes. Analysis revealed 4 themes: rationale for routine testing, barriers to testing and follow-up, enablers of testing and follow-up, and ideal system to enhance patient management. Critical barriers to Lp(a) testing included a perceived lack of guidance in testing and follow-up, and misperception that Lp(a)-mediated cardiovascular risk cannot be managed resulting in low confidence of healthcare professionals to detect and manage elevated Lp(a). Inadequate institutional support to alleviate workload and presumed patient aversion to testing further hindered Lp(a) testing. We identified enablers and strategies to testing and management of Lp(a), notably these were the need for hospital-wide adequate training and education, guidelines and risk management pathways applicable to local settings, integration of Lp(a) testing into existing clinical pathways for high-risk patients, and user-friendly decision aids for healthcare professionals. Effective education for healthcare professionals and optimised clinical workflows may help to address current knowledge gap and implementation barriers in the detection and management of elevated Lp(a) in hospital. Show less

Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway. Show less

High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer. Show less