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Women's Health (London, England) 2022Nipple pain is a common reason for premature cessation of breastfeeding. Despite the benefits of breastfeeding for both infant and mother, clinical support for problems... (Review)
Review
Nipple pain is a common reason for premature cessation of breastfeeding. Despite the benefits of breastfeeding for both infant and mother, clinical support for problems such as maternal nipple pain remains a research frontier. Maternal pharmaceutical treatments, and infant surgery and bodywork interventions are commonly recommended for lactation-related nipple pain without evidence of benefit. The pain is frequently attributed to mammary dysbiosis, candidiasis, or infant anatomic anomaly (including to diagnoses of posterior or upper lip-tie, high palate, retrognathia, or subtle cranial nerve abnormalities). Although clinical protocols universally state that improved fit and hold is the mainstay of treatment of nipple pain and wounds, the biomechanical parameters of pain-free fit and hold remain an omitted variable bias in almost all clinical breastfeeding research. This article reviews the research literature concerning aetiology, classification, prevention, and management of lactation-related nipple-areolar complex (NAC) pain and damage. Evolutionary and complex systems perspectives are applied to develop a narrative synthesis of the heterogeneous and interdisciplinary evidence elucidating nipple pain in breastfeeding women. Lactation-related nipple pain is most commonly a symptom of inflammation due to repetitive application of excessive mechanical stretching and deformational forces to nipple epidermis, dermis and stroma during milk removal. Keratinocytes lock together when mechanical forces exceed desmosome yield points, but if mechanical loads continue to increase, desmosomes may rupture, resulting in inflammation and epithelial fracture. Mechanical stretching and deformation forces may cause stromal micro-haemorrhage and inflammation. Although the environment of the skin of the nipple-areolar complex is uniquely conducive to wound healing, it is also uniquely exposed to environmental risks. The two key factors that both prevent and treat nipple pain and inflammation are, first, elimination of conflicting vectors of force during suckling or mechanical milk removal, and second, elimination of overhydration of the epithelium which risks moisture-associated skin damage. There is urgent need for evaluation of evidence-based interventions for the elimination of conflicting intra-oral vectors of force during suckling.
Topics: Breast Feeding; Female; Humans; Infant; Lactation; Mothers; Nipples; Pain
PubMed: 35343816
DOI: 10.1177/17455057221087865 -
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 -
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 -
Differentiation; Research in Biological... Nov 2023Fibroblast growth factor 20 (FGF20) is a neurotrophic factor and a member of the FGF9 subfamily. It was first identified in Xenopus embryos and was isolated shortly...
Fibroblast growth factor 20 (FGF20) is a neurotrophic factor and a member of the FGF9 subfamily. It was first identified in Xenopus embryos and was isolated shortly thereafter from the adult rat brain. Its receptors include FGFR4, FGFR3b, FGFR2b and the FGFRc splice forms. In adults it is highly expressed in the brain, while it is expressed in a variety of regions during embryonic development, including the inner ear, heart, hair placodes, mammary buds, dental epithelium and limbs. As a result of its wide-spread expression, FGF20 mouse mutants exhibit a variety of phenotypes including congenital deafness, lack of hair, small kidneys and delayed mammary ductal outgrowth. FGF20 is also associated with human diseases including Parkinson's Disease, cancer and hereditary deafness.
PubMed: 38007375
DOI: 10.1016/j.diff.2023.10.005 -
Cell Jun 2022X inactivation (XCI) is triggered by upregulation of XIST, which coats the chromosome in cis, promoting formation of a heterochromatic domain (Xi). XIST role beyond...
X inactivation (XCI) is triggered by upregulation of XIST, which coats the chromosome in cis, promoting formation of a heterochromatic domain (Xi). XIST role beyond initiation of XCI is only beginning to be elucidated. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSCs) and promotes emergence of highly tumorigenic and metastatic carcinomas. On the Xi, XIST deficiency triggers epigenetic changes and reactivation of genes overlapping Polycomb domains, including Mediator subunit MED14. MED14 overdosage results in increased Mediator levels and hyperactivation of the MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We further demonstrate that loss of XIST and Xi transcriptional instability is common among human breast tumors of poor prognosis. We conclude that XIST is a gatekeeper of human mammary epithelium homeostasis, thus unveiling a paradigm in the control of somatic cell identity with potential consequences for our understanding of gender-specific malignancies.
Topics: Breast Neoplasms; Cell Differentiation; Epigenesis, Genetic; Humans; Mediator Complex; Neoplastic Stem Cells; RNA, Long Noncoding; X Chromosome Inactivation
PubMed: 35597241
DOI: 10.1016/j.cell.2022.04.034 -
Cell Reports May 2022Tissue-resident macrophages adapt to local signals within tissues to acquire specific functions. Neoplasia transforms the tissue, raising the question as to how the...
Tissue-resident macrophages adapt to local signals within tissues to acquire specific functions. Neoplasia transforms the tissue, raising the question as to how the environmental perturbations contribute to tumor-associated macrophage (TAM) identity and functions. Combining single-cell RNA sequencing (scRNA-seq) with spatial localization of distinct TAM subsets by imaging, we discover that TAM transcriptomic programs follow two main differentiation paths according to their localization in the stroma or in the neoplastic epithelium of the mammary duct. Furthermore, this diversity is exclusively detected in a spontaneous tumor model and tracks the different tissue territories as well as the type of tumor lesion. These TAM subsets harbor distinct capacity to activate CD8+ T cells and phagocyte tumor cells, supporting that specific tumor regions, rather than defined activation states, are the major drivers of TAM plasticity and heterogeneity. The distinctions created here provide a framework to design cancer treatment targeting specific TAM niches.
Topics: Breast Neoplasms; Female; Humans; Macrophages; Transcriptome; Tumor-Associated Macrophages
PubMed: 35613577
DOI: 10.1016/j.celrep.2022.110865 -
Cell Jan 2022Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor...
Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.
Topics: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Differentiation; Cohort Studies; Disease Progression; Epithelial Cells; Epithelium; Extracellular Matrix; Female; Fibroblasts; Humans; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Phenotype; Single-Cell Analysis; Stromal Cells; Tumor Microenvironment
PubMed: 35063072
DOI: 10.1016/j.cell.2021.12.023 -
Modern Pathology : An Official Journal... Jan 2021Papillary neoplasms of the breast are a heterogeneous group of epithelial tumors nearly entirely composed of papillae. Their classification rests on the characteristics... (Review)
Review
Papillary neoplasms of the breast are a heterogeneous group of epithelial tumors nearly entirely composed of papillae. Their classification rests on the characteristics of the epithelium and the presence and distribution of the myoepithelial cells along the papillae and around the tumor. Papillary neoplasms of the breast can be diagnostically challenging, especially if only core needle biopsy (CNB) material is available. This review summarizes salient morphological and immunohistochemical features, clinical presentation, and differential diagnoses of papillary neoplasms of the breast. We include a contemporary appraisal of the upgrade rate to carcinoma (invasive carcinoma and ductal carcinoma in situ [DCIS]) and atypical hyperplasias in surgical excision specimens obtained following CNB diagnosis of papilloma without atypia, and a review of the available follow-up data in cases without immediate surgical excision.
Topics: Biopsy, Large-Core Needle; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Diagnosis, Differential; Epithelial Cells; Female; Humans; Hyperplasia; Neoplasm Grading; Papilloma, Intraductal; Retrospective Studies
PubMed: 33106592
DOI: 10.1038/s41379-020-00706-5 -
Nature Genetics Apr 2023Women with germline BRCA1 mutations (BRCA1) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1 is associated with premalignant changes in...
Women with germline BRCA1 mutations (BRCA1) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1 is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1 and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1 stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1 may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.
Topics: Female; Humans; Mutation; BRCA1 Protein; Breast Neoplasms; Cell Transformation, Neoplastic; Mammary Glands, Human; Carcinogenesis; Stromal Cells
PubMed: 36914836
DOI: 10.1038/s41588-023-01298-x -
Nature Oct 2020Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer. Here we use mouse models of breast and...
Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.
Topics: Animals; Breast Neoplasms; Chemotaxis; Disease Models, Animal; Disease Progression; Endothelial Cells; Endothelium; Female; Humans; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Male; Mice; Neoplasm Metastasis; Nerve Tissue Proteins; RNA, Double-Stranded; Receptors, Immunologic; Signal Transduction; Toll-Like Receptor 3; Tumor Cells, Cultured; Roundabout Proteins
PubMed: 32999457
DOI: 10.1038/s41586-020-2774-y