Project description:Aging increases breast cancer risk while an early first pregnancy reduces a woman’s life-long risk. While several studies have explored the effect of either aging or pregnancy on mammary stem/progenitor cells, the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single-cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a differentiated cell state. Importantly, we uncover a minority population of Il33-expressing epithelial cells that express both luminal and basal markers (i.e. hybrid), which accumulate in aged nulliparous mice but are significantly reduced in aged parous mice. Functionally, IL33 treatment of mammary epithelial cells from young mice phenocopies aged nulliparous epithelial cells, induces proliferation and promotes formation of organoids with Trp53 knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated imbalances in lineage integrity in the basal layer, including a decrease in Il33+ hybrid cells, that could potentially contribute to pregnancy-induced breast cancer protection.
Project description:There is a lack of systematic investigations of large-scale transcriptome patterns associated with normal breast development. Herein, we profiled whole-transcriptome (by microarrays) of normal mammary glands in female Sprague-Dawley rats, an animal model widely used in breast cancer research, across six distinctive developmental stages – pre-pubertal, peri-pubertal, pubertal, lactation, and adult parous and age-matched nulliparous.
Project description:Aging increases breast cancer risk while an early first pregnancy reduces a woman’s life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary epithelial cells (MECs), but the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a permanently differentiated cell state. Importantly, we uncover a minority population of Il33-expressing hybrid cells with high cellular potency that accumulate in aged nulliparous mice but is significantly reduced in aged parous mice. Functionally, IL33 treatment of basal, but not luminal, epithelial cells from young mice phenocopies aged nulliparous MECs and promotes formation of organoids with Tp53 knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated loss of lineage integrity in the basal layer through a decrease in Il33+ hybrid cells, potentially contributing to pregnancy-induced breast cancer protection.
Project description:We tested the gene expression difference between PDGFRa+ fibroblasts FACS sorted from nulliparous balb/c mouse mammary glands and 6 days post-weaning mammary glands
Project description:Gene expression, DNA and histone methylation profiles were performed on multiple cell types purified from normal human nulliparous and parous breast tissue using SAGE-seq, MSDK-seq and ChIP-seq [GSE26141].
Project description:Case-control study for the analysis of the gene expression profile of epithelial cells microdissected from normal breast tissues obtained from 17 parous and 7 nulliparous women free of breast pathology (controls), and 39 parous and 8 nulliparous women with history of breast cancer (cases). Keywords: genetic modifications
Project description:Case-control study for the analysis of the gene expression profile of epithelial cells microdissected from normal breast tissues obtained from 17 parous and 7 nulliparous women free of breast pathology (controls), and 39 parous and 8 nulliparous women with history of breast cancer (cases). Keywords: genetic modifications Four-condition experiment: nulliparous case, nulliparous control, parous case and parous control labeled with Cy5 and Universal human reference used as a common reference labeled with Cy3. Moderated t statistic was used as the basic statistic for significance analysis; it was computed for each probe and for each contrast. False discovery rate was controlled using the Benjamini and Hochberg. All genes with P value below a threshold of 0.05 were selected as differentially expressed, maintaining the proportion of false discoveries in the selected group below the threshold value, in this case 5%. Breast 11 parous control HuII, Breast 28 parous case HuII, and Breast 62 nulliparous control HuIII excluded: raw data is missing
Project description:Exposure to common environmental chemicals, including those found in personal care products has been linked to mammary cancer at high doses in animal models. Their effects at low doses at levels comparable to human exposure remain poorly understood. Using a Sprague-Dawley rat model, we investigated the effects of three prevalently used environmental chemicals – diethyl phthalate (DEP), methyl paraben (MPB), triclosan (TCS) – and their mixture (MIX) on the transcriptome of normal developing mammary at levels mimicking human exposure. Rats were exposed from birth to adulthood in parous and nulliparous settings. We used affymetrix arrays to assess the influence of diethyl phthalate (DEP), methyl paraben (MPB), triclosan (TCS) and their mixture (MIX) on global gene expression profiles in rat mammary tissues, using doses comparable to human exposure. Exposure was from birth to adulthood (postnatal day 1 – 180) in parous and nulliparous rats.
Project description:The objective of the study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women.