During puberty, a woman’s breasts are vulnerable to environmental damage (“window of vulnerability”). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.

Background: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top “hit” was chromatin opening at H3K9ac. Methods: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. Results: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. Conclusions: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.

Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.

Kämmerer et al., (2023) reviewed the trustworthiness of Reverse Transcription – Polymerase Chain Reaction (RT-PCR) and sought to solve the serious problems that remain challenging its use and the significance of its application for the diagnosis of COVID-19 infections. They proposed certain modifications which they argued will enable more precise and trustworthy diagnostic results. However, this paper has a clear focus on the technical aspect of RT-PCR, which is only one piece of the COVID-19 puzzle, while there are other equally important pieces still missing. In order to establish what could correctly be judged as a true positive diagnosis, one sharply distinct from a false positive diagnosis, it is necessary to consider additional details. We believe their recommendations amount only to a partial solution to the deeper problems their work implicates. We propose to look at the larger perspective: to start from the very beginning, that is the definition of COVID-19 disease.

Background: Clinical trials should benefit all people. Consequently, the National Cancer Institute expects cancer centers to accrue individuals to clinical trials in proportion to the cancer burden experienced by populations that live in their respective catchment areas; unfortunately, many cancer centers fail to meet this expectation. The person who gives consent for individuals in clinical trials frequently has significant contact with potential trial participants. We hypothesized that the race, ethnicity, and language of the consenter may have an important bearing on whether an individual chooses to participate in a clinical trial. Methods: We used mixed methods to investigate the impact of the socio-cultural background of the consenter on the decision of a potential research subject to participate in a clinical trial. Between 01/2018 and 02/2020, 205 women were approached in the sequential order they appeared in our breast clinic; of the 181 participants who agreed to complete the survey questionnaire, 94 (52%) were Northern European, non-Hispanic White (NE White), and 87 (48%) were Women-of-Color (WOC); this category includes participants who self-identified as Asian, Black, Hispanic/Latina, or Native American. Results: There were statistically significant differences according to the importance of the consenter’s characteristics in the decision to enroll or decline participation in the BCT. No NE White enroller (0%, n = 0) reported that consenter race was important versus 11% (n = 9) of WOC enrollers (p = 0.0009). Similarly, none of the NE White enrollers rated the consenter “looking like people in my community” as important versus 12% (n = 10) of the WOC enrollers (p = 0.0004). Conclusions: We find that consenter race and ethnicity are important for clinical trial diversity. Larger studies are needed to evaluate the generalizability of this finding.

Pregnancy-associated triple-negative breast cancer (PA-TNBC) is a highly aggressive, hard-to-treat malignancy, with increased risk linked to post-lactational mammary gland involution. To understand this, we used GeoMx Digital Spatial Profiler to analyze the transcriptional landscape of 46 treatment-naïve PA-TNBC tissues from 33 women (10 pre-involution/PRE; 23 post-involution/POST, diagnosed within 3 years of delivery), focusing on epithelial and microenvironmental changes. Our findings reveal that the most significant transcriptional differences between PRE and POST exist in non-invasive epithelia and during the transition to invasion. POST non-invasive epithelia showed distinct activation of inflammatory and developmental pathways, while transitioning to TNBC involved elevated chromatin remodeling and migration. Notably, the tumor microenvironment (TME) surrounding POST invasive epithelia featured the greatest immune cell infiltration yet also increased immune exhaustion. Pseudotime analysis highlighted the 1–2 year postpartum window as having the strongest inflammatory signaling. These results underline the need for early molecular detection in normal-appearing post-involution tissues and suggest that targeting the TME is a viable strategy for treating POST PA-TNBC.