Biology subjects

Baker, L. A.

Publications and source records attributed to Baker, L. A..

4 recordsLinked to original sources

bioRxiv2018

A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer.

Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Here, we have defined a molecular mechanism of action for ID4 in BLBC and the related disease highgrade serous ovarian cancer (HGSOV), by combining RIME proteomic analysis and ChIP-Seq mapping of genomic binding sites. Remarkably, these studies have revealed novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins ({gamma}H2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage and regulating DNA damage signalling. Clinical analysis demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair pathways. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOV.

cancer biology↗

bioRxiv2018

Single cell transcriptomics reveals molecular subtype and functional heterogeneity in models of breast cancer

Breast cancer has long been classified into a number of molecular subtypes that predict prognosis and therefore influence clinical treatment decisions. Cellular heterogeneity is also evident in breast cancers and plays a key role in the development, evolution and metastatic progression of many cancers. How clinical heterogeneity relates to cellular heterogeneity is poorly understood, so we approached this question using single cell gene expression analysis of well established in vitro and in vivo models of disease.\n\nTo explore the cellular heterogeneity in breast cancer we first examined a panel of genes that define the PAM50 classifier of molecular subtype. Five breast cancer cell line models (MCF7, BT474, SKBR3, MDA-MB-231, and MDA-MB-468) were selected as representatives of the intrinsic molecular subtypes (luminal A and B, basal-like, and Her2-enriched). Single cell multiplex RT-PCR was used to isolate and quantify the gene expression of single cells from each of these models, and the PAM50 classifier applied. Using this approach, we identified heterogeneity of intrinsic subtypes at single-cell level, indicating that cells with different subtypes exist within a cell line. Using the Chromium 10X system, this study was extended into thousands of cells from the MCF7 cell-line and an ER+ patient derived xenograft (PDX) model and again identified significant intra-tumour heterogeneity of molecular subtype.\n\nEstrogen Receptor (ER) is an important driver and therapeutic target in many breast cancers. It is heterogeneously expressed in a proportion of clinical cases but the significance of this to ER activity is unknown. Significant heterogeneity in the transcriptional activation of ER regulated genes was observed within tumours. This differential activation of the ER cistrome aligned with expression of two known transcriptional co-regulatory factors of ER (FOXA1 and PGR).\n\nTo examine the degree of heterogeneity for other important phenotypic traits, we used an unsupervised clustering approach to identify cellular sub-populations with diverse cancer associated transcriptional properties, such as: proliferation; hypoxia; and treatment resistance. In particular, we show that we can identify two distinct sub-populations of cells that may have denovo resistance to endocrine therapies in a treatment naive PDX model of ER+ breast cancer. One of these consists of cells with a non-proliferative transcriptional phenotype that is enriched for transcriptional properties of ERBB2 tumours. The other is heavily enriched for components of the primary cilia. Gene regulatory networks were used to identify transcription factor regulons that are active in each cell, leading us to identify potential transcriptional drivers (such as E2F7, MYB and RFX3) of the cilia associated endocrine resistant cells. This rare subpopulation of cells also has a highly heterogenous mix of intrinsic subtypes highlighting a potential role of intra-tumour subtype heterogeneity in endocrine resistance and metastatic potential.\n\nOverall, These results suggest a high degree of cellular heterogeneity within breast cancer models, even cell lines, that can be functionally dissected into sub-populations of cells with transcriptional phenotypes of potential clinical relevance.

cancer biology↗

bioRxiv2017

Longitudinal Analysis of Particulate Air Pollutants and Adolescent Delinquent Behavior in Southern California

Animal experiments and cross-sectional human studies have linked particulate matter (PM) with increased behavioral problems. We conducted a longitudinal study to examine whether the trajectories of delinquent behavior are affected by PM2.5 (PM with aerodynamic diameter [≤]2.5 m) exposures before and during adolescence. We used the parent-reported Child Behavior Checklist at age 9-18 with repeated measures every ~2-3 years (up to 4 behavioral assessments) on 682 children from the Risk Factors for Antisocial Behavior Study conducted in a multi-ethnic cohort of twins born in 1990-1995. Based on prospectively-collected residential addresses and a spatiotemporal model of ambient air concentrations in Southern California, monthly PM2.5 estimates were aggregated to represent long-term (1-, 2-, 3-year average) exposures preceding baseline and cumulative average exposure until the last assessment. Multilevel mixed-effects models were used to examine the association between PM2.5 exposure and individual trajectories of delinquent behavior, adjusting for within-family/within-individual correlations and potential confounders. We also examined whether psychosocial factors modified this association. The results suggest that PM2.5 exposure at baseline and cumulative exposure during follow-up was significantly associated (p<0.05) with increased delinquent behavior. The estimated effect sizes (per interquartile increase of PM2.5 by 3.12-5.18 {micro}g/m3) were equivalent to the difference in delinquency scores between adolescents who are 3.5-4 years apart in age. The adverse effect was stronger in families with unfavorable parent-to-child relationships, increased parental stress or maternal depressive symptoms. Overall, these findings suggest long-term PM2.5 exposure may increase delinquent behavior of urban-dwelling adolescents, with the resulting neurotoxic effect aggravated by psychosocial adversities.

epidemiology↗

bioRxiv2017

Socioeconomic Disparities and Sexual Dimorphism in Neurotoxic Effects of Ambient Fine Particles on Youth IQ: A Longitudinal Analysis

Mounting evidence indicates that early-life exposure to particulate air pollutants pose threats to childrens cognitive development, but studies about the neurotoxic effects associated with exposures during adolescence remain unclear. We examined whether exposure to ambient fine particles (PM2.5) at residential locations affects intelligence quotient (IQ) during pre-/early-adolescence (ages 9-11) and emerging adulthood (ages 18-20) in a demographically-diverse population (N = 1,360) residing in Southern California. Increased ambient PM2.5 levels were associated with decreased IQ scores. This association was more evident for Performance IQ (PIQ), but less for Verbal IQ, assessed by the Wechsler Abbreviated Scale of Intelligence. For each inter-quartile (7.73 g/m3) increase in one-year PM2.5 preceding each assessment, the average PIQ score decreased by 3.08 points (95% confidence interval = [-6.04, -0.12]) accounting for within-family/within-individual correlations, demographic characteristics, family socioeconomic status (SES), parents cognitive abilities, neighborhood characteristics, and other spatial confounders. The adverse effect was 150% greater in low SES families and 89% stronger in males, compared to their counterparts. Better understanding of the social disparities and sexual dimorphism in the adverse PM2.5-IQ effects may help elucidate the underlying mechanisms and shed light on prevention strategies.

epidemiology↗