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Molecular and cellular alterations associated with long-term murine mammary cancer prevention following short-term tamoxifen chemoprevention indicate luminal progenitor cells as targets

ABSTRACT: Limited term administration of tamoxifen for 2-8 years results in long-term prevention of estrogen receptor positive (ER+) breast cancer as demonstrated in several clinical trials. How the memory of tamoxifen is initiated and maintained, as well as which cells are involved and what molecular messages are transmitted, is undefined. Understanding these features of this robust chemopreventive agent will lead to significant advancement in our knowledge of how a healthy breast environment is supported. The purpose of this study was to determine the molecular message that reflects a long-term and efficacious memory of tamoxifen. We used microarrays to identify genes with a significant long-term alteration in expression level following a short-term exposure to tamoxifen as a chemopreventive.

ORGANISM(S): Mus musculus

PROVIDER: GSE43809 | GEO | 2018/01/02

SECONDARY ACCESSION(S): PRJNA187485

REPOSITORIES: GEO

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Project description:We utilized an unbiased RNA-sequencing approach to uncover genes in the dorsal hippocampus that are differentially expressed under conditions where exercise benefits are maintained throughout sedentary delay periods and enable the formation of long-term memory and synaptic plasticity. Engagement in different exercise parameters resulted in a diverse transcriptional profile as defined by differences in the number, pattern, and type of genes up and down-regulated. To identify genes that play a critical role in cognitive enhancement, we next focused our attention on exercise groups that enable robust long-term memory formation under inadequate subthreshold acquisition sessions of the hippocampus-dependent object location memory task. By intersecting up regulated genes when exercise facilitated learning, we identify potential regulators of learning and targets for memory enhancement. We identify a gene coding for a type 1 membrane receptor and kinase for the TGF-β family of signaling molecules, Acvr1c as one of few genes showing upregulation in conditions where exercise enabled the formation of long-term memory, indicating a gate-type role for Acvr1c in memory consolidation. In addition to overall gene expression levels, we identify potential regulators upstream of gene targets within the window for cognitive enhancement. Additionally, we use three complementary analyses to examine the mechanisms responsible for maintaining the ‘molecular memory window’ for exercise utilizing up regulated differentially expressed genes compared to sedentary controls. These analyses include: gene coexpression network analysis to identify potential hub genes for each exercise condition, predicted pathways altered by exercise, and gene ontology enrichment analysis of cellular components altered by exercise. Together, results identify Acvr1c as one of few genes up regulated only under conditions where exercise enabled the formation of long-term memory and synaptic plasticity, suggesting a role for Acvr1c in facilitation of memory consolidation. Follow up experiments manipulating ACVR1C function, find that it serves as an essential bidirectional regulator of long-term memory formation capable of alleviating impairments in hippocampus-dependent memory and synaptic plasticity associated with age and Alzheimer’s Disease.

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Molecular and cellular alterations associated with long-term murine mammary cancer prevention following short-term tamoxifen chemoprevention indicate luminal progenitor cells as targets

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