Several studies have sought to identify novel transcriptional biomarkers in normal breast or breast microenvironment to predict tumor risk and prognosis. However, systematic efforts to evaluate intra-individual variability of gene expression within normal breast have not been reported. This study analyzed the microarray gene expression data of 288 samples from 170 women in the Normal Breast Study (NBS), wherein multiple histologically normal breast samples were collected from different block regions and different sections at a given region. Intra-individual differences in global gene expression and selected gene expression signatures were quantified and evaluated in association with other patient-level factors. We found that intra-individual reliability was relatively high in global gene expression, but differed by signatures, with composition-related signatures (i.e., stroma) having higher intra-individual variability and tumorigenesis-related signatures (i.e., proliferation) having lower intra-individual variability. Histological stroma composition was the only factor significantly associated with heterogeneous breast tissue (defined as > median intra-individual variation; high nuclear density, odds ratio [OR] = 3.42, 95% confidence interval [CI] = 1.15-10.15; low area, OR = 0.29, 95% CI = 0.10-0.86). Other factors suggestively influencing the variability included age, BMI, and adipose nuclear density. Our results underscore the importance of considering intra-individual variability in tissue-based biomarker development, and have important implications for normal breast research.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the pressing contemporary public health challenges. Investigations into the genomic structure of SARS-CoV-2 may inform ongoing vaccine development efforts and/or provide insights into vaccine efficacy to fight against COVID-19. Evolutionary analysis of 540 genomes spanning 20 different countries/territories was conducted and revealed an increase in the genomic divergence across successive generations. The ancestor of the phylogeny was found to be the isolate from the 2019/2020 Wuhan outbreak. Its transmission was outlined across 20 countries/territories as per genomic similarity. Our results demonstrate faster evolving variations in the genomic structure of SARS-CoV-2 when compared to the isolates from early stages of the pandemic. Genomic alterations were predominantly located and mapped onto the reported vaccine candidates of structural genes, which are the main targets for vaccine candidates. S protein showed 34, N protein 25, E protein 2, and M protein 3 amino acid variations in 246 genomes among 540. Among identified mutations, 23 in S protein, 1 in E, 2 from M, and 7 from N protein were mapped with the reported vaccine candidates explaining the possible implications on universal vaccines. Hence, potential target regions for vaccines would be ideally chosen from the structural regions of the genome that lack high variation. The increasing variations in the genome of SARS-CoV-2 together with our observations in structural genes have important implications for the efficacy of a successful universal vaccine against SARS-CoV-2.

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.

Maternal-infant equilibrium occurs when cord blood docosahexaenoic acid (DHA) is less than or equal to maternal DHA at delivery. Equilibrium may be an indicator of sufficient DHA for optimal fetal and infant neurodevelopment. The purpose of this study was to test the effect of maternal DHA supplementation on equilibrium status and fetal neurodevelopment.

The need for routine surgical excision of a radial sclerosing lesions (RSL) of the breast identified on percutaneous biopsy remains controversial, as contemporary upgrade rates are lower than historically cited.

Delayed age-related lobular involution has been previously associated with elevated breast cancer risk. However, intraindividual variability in epithelial involution status within a woman is undefined. We developed a novel measure of age-related epithelial involution, density of epithelial nuclei in epithelial areas using digital image analysis in combination with stromal characteristics (percentage of section area comprising stroma). Approximately 1800 hematoxylin and eosin stained sections of benign breast tissue were evaluated from 416 participants having breast surgery for cancer or benign conditions. Two to sixteen slides per woman from different regions of the breast were studied. Epithelial involution status varied within a woman and as a function of stromal area. Percentage stromal area varied between samples from the same woman (median difference between highest and lowest stromal area within a woman was 7.5%, but ranged from 0.01 to 86.7%). Restricting to women with at least 10% stromal area (N = 317), epithelial nuclear density decreased with age (-637.1 cells/mm2 per decade of life after age 40, p < 0.0001), increased with mammographic density (457.8 cells/mm2 per increasing BI-RADs density category p = 0.002), and increased non-significantly with recent parity, later age at first pregnancy, and longer and more recent oral contraceptive use. These associations were attenuated in women with mostly fat samples (<10% stroma (N = 99)). Thirty-one percent of women evaluated had both adequate stroma (≥10%) and mostly fat (<10% stroma) regions of breast tissue, with the probability of having both types increasing with the number breast tissue samplings. Several breast cancer risk factors are associated with elevated age-related epithelial content, but associations depend upon stromal context. Stromal characteristics appear to modify relationships between risk factor exposures and breast epithelial involution.

The University of Kansas Cancer Center (KU Cancer Center) recently developed a data warehouse to Organize and Prioritize Trends to Inform KU Cancer Center (OPTIK). The OPTIK database aggregates and standardizes data collected across the bistate catchment area served by the KU Cancer Center. To improve the usability of the OPTIK database, we developed shinyOPTIK, a user-friendly, interactive web application for visualizing cancer risk factor and mortality rate data across the KU Cancer Center Catchment area.