Ormiston, K. | Search bioRxiv

bioRxiv2025

Estrogen Signaling During Abrupt Involution Leads to Long-Term Metabolic Dysfunction Similar to Estrogen Receptor Negative Breast Cancer

Epidemiological data links lack of breastfeeding with increased risk of breast cancer. Breast tissue undergoes remodeling to pre-pregnancy state after birth through involution. Long-term breastfeeding leads to gradual involution (GI). Lack of breastfeeding leads to abrupt involution (AI). While estrogen impacts repopulation of adipocytes, AI causes several precancerous changes in the mouse mammary gland. The impact of AI on adipocyte repopulation and metabolism is yet to be elucidated. ObjectivesTo investigate effects of AI on mammary gland metabolism and its potential link to breast cancer. MethodsAt partum (day 0), FVB/n dams were randomized to AI or GI and standardized to 6 pups. AI mice had pups removed on day 7 postpartum to mimic short-term breastfeeding. GI mice had 3 pups each were removed on day 28 and 31 postpartum to mimic gradual weaning. Mammary glands were harvested on day 28, 56, and 120 postpartum. Subset of AI mice had long-term sustained release tamoxifen placed subscapular on day 8 postpartum. Metabolic changes were assessed using: 1) transcriptional; 2) functional; 3) oxidative stress; and 4) metabolites analysis. ResultsDay 28 GI glands sustains/continues milk synthesis pathways impacting metabolic comparison with day28 AI glands. Day 28 AI when compared to day 56 GI showed upregulation of estrogen signaling, neutrophil degranulation, glucose metabolism, RNA synthesis, and down regulation of adipogenesis and glycolysis. At day 120, AI glands had downregulation of oxidative phosphorylation and upregulation of mitochondria dysfunction similar to pregnancy associated estrogen receptor negative breast cancer. Tamoxifen treatment of AI dams showed metabolic pathways and estrogen signaling similar to that of GI glands on day 28. ConclusionEarly metabolic phenotypes in AI and GI glands may be caused by differences in adipocyte repopulation related to estrogen signaling. Long-term metabolic effects of AI lead to similar metabolic effects found in breast cancer.

cancer biology↗

bioRxiv2020

Response preparation involves a release of intracortical inhibition in task-irrelevant muscles

Action preparation involves widespread modulation of motor system excitability, but the precise mechanisms are unknown. In this study, we investigated whether intracortical inhibition changes in task-irrelevant muscle representations during action preparation. We used transcranial magnetic stimulation (TMS) combined with electromyography in healthy human adults to measure motor evoked potentials (MEPs) and cortical silent periods (CSPs) in task-irrelevant muscles during the preparatory period of simple delayed response tasks. In Experiment 1, participants responded with the left-index finger in one task condition and the right-index finger in another task condition, while MEPs and CSPs were measured from the contralateral non-responding and tonically contracted index finger. During Experiment 2, participants responded with the right pinky finger while MEPs and CSPs were measured from the tonically contracted left-index finger. In both experiments, MEPs and CSPs were compared between the task preparatory period and a resting intertrial baseline. The CSP duration during response preparation decreased from baseline in every case. A laterality difference was also observed in Experiment 1, with a greater CSP reduction during the preparation of left finger responses compared to right finger responses. MEP amplitudes showed no modulation during movement preparation in any of the three response conditions. These findings indicate cortical inhibition associated with task-irrelevant muscles is transiently released during action preparation and implicate a novel mechanism for the controlled and coordinated release of motor cortex inhibition. New & NoteworthyIn this study we observed the first evidence of a release of intracortical inhibition in task-irrelevant muscle representations during response preparation. We applied transcranial magnetic stimulation to elicit cortical silent periods in task-irrelevant muscles during response preparation and observed a consistent decrease in the silent period duration relative to a resting baseline. These findings address the question of whether cortical mechanisms underlie widespread modulation in motor excitability during response preparation.

neuroscience↗