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Current Opinion in Cell Biology Oct 2020The mammary gland is a highly dynamic tissue that undergoes repeated cycles of growth and involution during pregnancy and menstruation. It is also the site from which... (Review)
Review
The mammary gland is a highly dynamic tissue that undergoes repeated cycles of growth and involution during pregnancy and menstruation. It is also the site from which breast cancers emerge. Organoids provide an in vitro model that preserves several of the cellular, structural, and microenvironmental features that dictate mammary gland function in vivo and have greatly advanced our understanding of glandular biology. Their tractability for genetic manipulation, live imaging, and high throughput screening have facilitated investigation into the mechanisms of glandular morphogenesis, structural maintenance, tumor progression, and invasion. Opportunities remain to enhance cellular and structural complexity of mammary organoid models, including incorporating additional cell types and hormone signaling.
Topics: Animals; Breast Neoplasms; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Models, Biological; Morphogenesis; Organoids
PubMed: 32535255
DOI: 10.1016/j.ceb.2020.05.003 -
Seminars in Cell & Developmental Biology Jun 2021Our understanding of the molecular events underpinning the development of mammalian organ systems has been increasing rapidly in recent years. With the advent of new and... (Review)
Review
Our understanding of the molecular events underpinning the development of mammalian organ systems has been increasing rapidly in recent years. With the advent of new and improved next-generation sequencing methods, we are now able to dig deeper than ever before into the genomic and epigenomic events that play critical roles in determining the fates of stem and progenitor cells during the development of an embryo into an adult. In this review, we detail and discuss the genes and pathways that are involved in mammary gland development, from embryogenesis, through maturation into an adult gland, to the role of pregnancy signals in directing the terminal maturation of the mammary gland into a milk producing organ that can nurture the offspring. We also provide an overview of the latest research in the single-cell genomics of mammary gland development, which may help us to understand the lineage commitment of mammary stem cells (MaSCs) into luminal or basal epithelial cells that constitute the mammary gland. Finally, we summarize the use of 3D organoid cultures as a model system to study the molecular events during mammary gland development. Our increased investigation of the molecular requirements for normal mammary gland development will advance the discovery of targets to predict breast cancer risk and the development of new breast cancer therapies.
Topics: Animals; Cell Differentiation; Epithelial Cells; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human
PubMed: 33082117
DOI: 10.1016/j.semcdb.2020.09.014 -
Physiological Reviews Apr 2020The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by... (Review)
Review
The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor cells. Both short- and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging diversity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.
Topics: Animals; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Transformation, Neoplastic; Female; Gene Expression Regulation, Developmental; Humans; Mammary Glands, Animal; Mammary Glands, Human; Morphogenesis; Neoplastic Stem Cells; Phenotype; Signal Transduction; Stem Cells; Transcription Factors; Tumor Microenvironment
PubMed: 31539305
DOI: 10.1152/physrev.00040.2018 -
The EMBO Journal Jun 2021To examine global changes in breast heterogeneity across different states, we determined the single-cell transcriptomes of > 340,000 cells encompassing normal breast,...
To examine global changes in breast heterogeneity across different states, we determined the single-cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1 tissue, the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the normal breast microenvironment revealed striking changes in the stroma of post-menopausal women. Single-cell profiling of 34 treatment-naive primary tumors, including estrogen receptor (ER) , HER2 , and triple-negative breast cancers, revealed comparable diversity among cancer cells and a discrete subset of cycling cells. The transcriptomes of preneoplastic BRCA1 tissue versus tumors highlighted global changes in the immune microenvironment. Within the tumor immune landscape, proliferative CD8 T cells characterized triple-negative and HER2 cancers but not ER tumors, while all subtypes comprised cycling tumor-associated macrophages, thus invoking potentially different immunotherapy targets. Copy number analysis of paired ER tumors and lymph nodes indicated seeding by genetically distinct clones or mass migration of primary tumor cells into axillary lymph nodes. This large-scale integration of patient samples provides a high-resolution map of cell diversity in normal and cancerous human breast.
Topics: Breast Neoplasms; CD8-Positive T-Lymphocytes; Carcinogenesis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Mammary Glands, Human; RNA-Seq; Single-Cell Analysis; Tumor Microenvironment
PubMed: 33950524
DOI: 10.15252/embj.2020107333 -
Neoplasia (New York, N.Y.) Dec 2020The cellular heterogeneity of breast cancers still represents a major therapeutic challenge. The latest genomic studies have classified breast cancers in distinct... (Review)
Review
The cellular heterogeneity of breast cancers still represents a major therapeutic challenge. The latest genomic studies have classified breast cancers in distinct clusters to inform the therapeutic approaches and predict clinical outcomes. The mammary epithelium is composed of luminal and basal cells, and this seemingly hierarchical organization is dependent on various stem cells and progenitors populating the mammary gland. Some cancer cells are conceptually similar to the stem cells as they can self-renew and generate bulk populations of nontumorigenic cells. Two models have been proposed to explain the cell of origin of breast cancer and involve either the reprogramming of differentiated mammary cells or the dysregulation of mammary stem cells or progenitors. Both hypotheses are not exclusive and imply the accumulation of independent mutational events. Cancer stem cells have been isolated from breast tumors and implicated in the development, metastasis, and recurrence of breast cancers. Recent advances in single-cell sequencing help deciphering the clonal evolution within each breast tumor. Still, few clinical trials have been focused on these specific cancer cell populations.
Topics: Animals; Breast Neoplasms; Disease Models, Animal; Disease Susceptibility; Female; Humans; Incidence; Mammary Glands, Human; Mice; Neoplasm Staging; Neoplastic Stem Cells; Risk Assessment; Stem Cells
PubMed: 33142233
DOI: 10.1016/j.neo.2020.09.009 -
Cancer Letters Sep 2021Transgenic breast cancer mouse models are critical tools for preclinical studies of human breast cancer. Genetic editing of the murine mammary gland allows for modeling...
Transgenic breast cancer mouse models are critical tools for preclinical studies of human breast cancer. Genetic editing of the murine mammary gland allows for modeling of abnormal genetic events frequently found in human breast cancers. Genetically engineered mouse models (GEMMs) of breast cancer employ tissue-specific genetic manipulation for tumorigenic induction within the mammary tissue. Under the transcriptional control of mammary-specific promoters, transgenic mouse models can simulate spontaneous mammary tumorigenesis by expressing one or more putative oncogenes, such as MYC, HRAS, and PIK3CA. Alternatively, the Cre-Lox system allows for tissue-specific deletion of tumor suppressors, such as p53, Rb1, and Brca1, or specific knock-in of putative oncogenes. Thus, GEMMs can be designed to implement one or more genetic events to induce mammary tumorigenesis. Features of GEMMs, such as age of transgene expression, breeding quality, tumor latency, histopathological characteristics, and propensity for local and distant metastasis, are variable and strain-dependent. This review aims to summarize currently available transgenic breast cancer mouse models that undergo spontaneous mammary tumorigenesis upon genetic manipulation, their varying characteristics, and their individual genetic manipulations that model aberrant signaling events observed in human breast cancers.
Topics: Animals; Breast Neoplasms; Carcinogenesis; Disease Models, Animal; Female; Humans; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice, Transgenic
PubMed: 34090924
DOI: 10.1016/j.canlet.2021.05.027 -
Microbiology Spectrum Feb 2022Mastitis, a highly prevalent disease in dairy cows, is commonly caused by local infection of the mammary gland. Our previous studies have suggested that the gut...
Mastitis, a highly prevalent disease in dairy cows, is commonly caused by local infection of the mammary gland. Our previous studies have suggested that the gut microbiota plays an important role in the development of mastitis in mice. However, the effects of rumen microbiota on bovine mastitis and the related mechanisms remain unclear. In this study, we assessed the effects and mechanisms of rumen microbiota on bovine mastitis based on the subacute rumen acidosis (SARA) model induced by feeding Holstein Frisian cows a high-concentrate diet for 8 weeks. Then, the inflammatory responses in the mammary gland and the bacterial communities of rumen fluid, feces, and milk were analyzed. The results showed that SARA induced mastitis symptoms in the mammary gland; activated a systemic inflammatory response; and increased the permeability of the blood-milk barrier, gut barrier, and rumen barrier. Further research showed that lipopolysaccharides (LPS), derived from the gut of SARA cows, translocated into the blood and accumulated in the mammary glands. Furthermore, the abundance of was increased in the rumen of SARA cows, and mastitis was induced by oral administration of in lactating mice. In conclusion, our findings suggested that mastitis is induced by exogenous pathogenic microorganisms as well as by endogenous pathogenic factors. Specifically, the elevated abundance of in the rumen and LPS translocation from the rumen to the mammary gland were important endogenous factors that induced mastitis. Our study provides a foundation for novel therapeutic strategies that target the rumen microbiota in cow mastitis. Mastitis is a common and frequently occurring disease of humans and animals, especially in dairy farming, which has caused huge economic losses and brought harmful substance residues, drug-resistant bacteria, and other public health risks. The traditional viewpoint indicates that mastitis is mainly caused by exogenous pathogenic bacteria infecting the mammary gland. Our study found that the occurrence of mastitis was induced by the endogenous pathway. Evidence has shown that rumen-derived LPS enters the mammary gland through blood circulation, damaging the blood-milk barrier and then inducing inflammation of the mammary gland in cows. In addition, a higher abundance of in the rumen was closely associated with the development of mastitis. This study provides a basis for novel therapeutic strategies that exploit the rumen microbiota against mastitis in cows.
Topics: Animals; Bacterial Translocation; Cattle; Feces; Female; Gastrointestinal Microbiome; Lactation; Mammary Glands, Animal; Mastitis, Bovine; Milk; Rumen; Stenotrophomonas
PubMed: 35196821
DOI: 10.1128/spectrum.02512-21 -
TheScientificWorldJournal 2021Breast cancer is the highest public detected cancer among female population in the majority of countries worldwide. Breast self-examination (BSE) is a useful screening...
Breast cancer is the highest public detected cancer among female population in the majority of countries worldwide. Breast self-examination (BSE) is a useful screening tool to empower women and raise awareness about their breast tissues and help detect any breast abnormalities when they occur. This study aimed to assess the level of female university students' knowledge and practice of BSE. A self-administered questionnaire was used to assess the knowledge about breast cancer and related items, and an observation checklist was used to test practicing BSE using a breast simulator. Eighty-six students participated in the study, 58.1% studying nursing and 41.9% studying clinical nutrition in the third (40.7%) or the fourth level (59.3%). Of them, 24.4% had previous family history of breast cancer. The majority of the students (80.2%) had previous information about breast cancer acquired from different sources, university studies (57%), the Internet (45%), and social media (41%). Findings showed good scores (≥70%) regarding signs and symptoms and risk factors of breast cancer; however, low knowledge scores (<70%) were detected regarding general knowledge about breast cancer disease, methods of early detection and management, and applying steps of practicing BSE. Roughly all the students (96.5%) have heard about BSE, and 69.8% knew the time to do BSE; however, only 31.4% practice it regularly. Three barriers to practice were dominant among students who do not have a breast problem (39.7%), do not know how to do it (37.9%), and being busy 31%. On the other hand, breast cancer early detection purpose and the presence of family history of breast cancer were considered facilitators to regular practice BSE. A statistically significant relationship existed between knowledge about the steps of applying the BSE and regular practicing. A training program should be implemented to increase the level of awareness about BC and practicing BSE.
Topics: Adult; Breast Neoplasms; Breast Self-Examination; Cross-Sectional Studies; Early Detection of Cancer; Female; Health Knowledge, Attitudes, Practice; Humans; Mammary Glands, Human; Middle East; Risk Factors; Students; Surveys and Questionnaires; Universities
PubMed: 34007246
DOI: 10.1155/2021/6640324 -
Nature Communications Apr 2020Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid...
Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.
Topics: Adult; BRCA1 Protein; Breast Neoplasms; Cell Culture Techniques; Cell Differentiation; Cell Lineage; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Mammary Glands, Human; Middle Aged; Organoids; Single-Cell Analysis; Stem Cells; Transforming Growth Factor beta; Young Adult; p38 Mitogen-Activated Protein Kinases
PubMed: 32249764
DOI: 10.1038/s41467-020-15548-7