Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

Li, Carman Man-Chung; Shapiro, Hana Kobayashi; Tsiobikas, Christina; Selfors, Laura M.; Chen, Huidong; Rosenbluth, Jennifer M.; Moore, Kaitlin; Gupta, K.; Gray, G. Kenneth; Oren, Yaara; Steinbaugh, Michael J.; Guerriero, Jennifer L.; Pinello, Luca; Regev, Aviv; Brugge, Joan S.

doi:10.1016/j.celrep.2020.108566

Cited by 82 publications

(64 citation statements)

References 154 publications

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“…Given that the genes for these keratins, in addition to KRT19 , are proximally located to one another on chromosome 17 suggests that they may be co-regulated in an age-dependent manner. Our data were consistent with scRNA sequencing from aging mammary pads of 7 inbred mice ( Li et al., 2020 ). Utilizing the age-dependent genes from Li et al.…”

Section: Discussionsupporting

confidence: 87%

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Deep proteome profiling of human mammary epithelia at lineage and age resolution

Hinz¹,

Manousopoulou

Miyano³

et al. 2021

iScience

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Summary Age is the major risk factor in most carcinomas, yet little is known about how proteomes change with age in any human epithelium. We present comprehensive proteomes comprised of >9,000 total proteins and >15,000 phosphopeptides from normal primary human mammary epithelia at lineage resolution from ten women ranging in age from 19 to 68 years. Data were quality controlled and results were biologically validated with cell-based assays. Age-dependent protein signatures were identified using differential expression analyses and weighted protein co-expression network analyses. Upregulation of basal markers in luminal cells, including KRT14 and AXL, were a prominent consequence of aging. PEAK1 was identified as an age-dependent signaling kinase in luminal cells, which revealed a potential age-dependent vulnerability for targeted ablation. Correlation analyses between transcriptome and proteome revealed age-associated loss of proteostasis regulation. Age-dependent proteome changes in the breast epithelium identified heretofore unknown potential therapeutic targets for reducing breast cancer susceptibility.

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Section: Discussionsupporting

confidence: 87%

“…Our data were consistent with scRNA sequencing from aging mammary pads of 7 inbred mice ( Li et al., 2020 ). Utilizing the age-dependent genes from Li et al. (2020) , we identified 160 homologs in our human TMT-MS data.…”

Section: Discussionsupporting

confidence: 87%

Deep proteome profiling of human mammary epithelia at lineage and age resolution

Hinz¹,

Manousopoulou

Miyano³

et al. 2021

iScience

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“…Exploration of molecular heterogeneity among individual mammary cells at a global level has revealed different levels of diversity within the luminal and basal compartments during mammary ontogeny that were not possible to uncover using bulk RNA-seq methodology. Recent single cell data also suggest that both epithelial compartments together with the surrounding stroma change upon aging [ 47 ]. Although there are some differences in the epithelial clustering apparent between different studies, this likely reflects the cell preparation, depth of sequencing, and the precise algorithms used for bioinformatic analyses.…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptome atlas of mouse mammary epithelial cells across development

et al. 2021

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Background Heterogeneity within the mouse mammary epithelium and potential lineage relationships have been recently explored by single-cell RNA profiling. To further understand how cellular diversity changes during mammary ontogeny, we profiled single cells from nine different developmental stages spanning late embryogenesis, early postnatal, prepuberty, adult, mid-pregnancy, late-pregnancy, and post-involution, as well as the transcriptomes of micro-dissected terminal end buds (TEBs) and subtending ducts during puberty. Methods The single cell transcriptomes of 132,599 mammary epithelial cells from 9 different developmental stages were determined on the 10x Genomics Chromium platform, and integrative analyses were performed to compare specific time points. Results The mammary rudiment at E18.5 closely aligned with the basal lineage, while prepubertal epithelial cells exhibited lineage segregation but to a less differentiated state than their adult counterparts. Comparison of micro-dissected TEBs versus ducts showed that luminal cells within TEBs harbored intermediate expression profiles. Ductal basal cells exhibited increased chromatin accessibility of luminal genes compared to their TEB counterparts suggesting that lineage-specific chromatin is established within the subtending ducts during puberty. An integrative analysis of five stages spanning the pregnancy cycle revealed distinct stage-specific profiles and the presence of cycling basal, mixed-lineage, and 'late' alveolar intermediates in pregnancy. Moreover, a number of intermediates were uncovered along the basal-luminal progenitor cell axis, suggesting a continuum of alveolar-restricted progenitor states. Conclusions This extended single cell transcriptome atlas of mouse mammary epithelial cells provides the most complete coverage for mammary epithelial cells during morphogenesis to date. Together with chromatin accessibility analysis of TEB structures, it represents a valuable framework for understanding developmental decisions within the mouse mammary gland.

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“…A recent single cell RNA-seq analysis comparing mammary glands from young (3-4 month-old) and aged (13-14 month-old) virgin mice revealed age-dependent alterations in cell type composition and gene expression that potentially reflect age-associated hormonal changes [192]. The proportion of hormone-sensing cells decreases with age and their transcriptomic profile is characterized by the up-regulated expression of Tph1 (encoding tryptophan hydroxylase 1) and Arg1 (encoding arginase 1).…”

Section: Main Molecular Features Of Erα + Luminal Cellsmentioning

confidence: 99%

Estrogen receptor-α signaling in post-natal mammary development and breast cancers

Rusidzé

Adlanmérini

Chantalat

et al. 2021

Cell. Mol. Life Sci.

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Abstract17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.

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Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

Cited by 82 publications

References 154 publications

Deep proteome profiling of human mammary epithelia at lineage and age resolution

Deep proteome profiling of human mammary epithelia at lineage and age resolution

Single cell transcriptome atlas of mouse mammary epithelial cells across development

Estrogen receptor-α signaling in post-natal mammary development and breast cancers

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