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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 -
Archives of Pathology & Laboratory... May 2009The pathologist evaluating breast biopsy specimens sometimes encounters nonneoplastic alterations of the mammary epithelium that raise the differential diagnosis of... (Review)
Review
CONTEXT
The pathologist evaluating breast biopsy specimens sometimes encounters nonneoplastic alterations of the mammary epithelium that raise the differential diagnosis of atypia. Because the identification of atypical ductal hyperplasia of the breast has significant clinical implications, it is important to correctly recognize its nonneoplastic morphologic mimics.
OBJECTIVE
To highlight a spectrum of physiologic and treatment-related changes that can occur in the mammary epithelium and to discuss the differential diagnosis with true atypia.
DATA SOURCES
A comprehensive review of the published English literature on physiologic and treatment-related changes of the breast epithelium was performed.
CONCLUSIONS
Among physiologic alterations of the ductal epithelium, luteal-phase changes and secretory changes can sometimes be overinterpreted as atypical. Treatment-related changes, secondary to chemotherapy and radiation, can pose a major diagnostic challenge and their misinterpretation as neoplastic carries major clinical consequences. Familiarity with the morphology of both physiologic and treatment-related alterations of the mammary epithelium is essential to avoid misdiagnosis.
Topics: Antineoplastic Agents; Biopsy; Breast; Breast Diseases; Diagnosis, Differential; Female; Humans; Hyperplasia; Mammary Glands, Human; Radiotherapy
PubMed: 19415946
DOI: 10.5858/133.5.722 -
Advances in Experimental Medicine and... 2019Adult female mammals are endowed with the unique ability to produce milk for nourishing their newborn offspring. Milk is secreted on demand by the mammary gland, an... (Review)
Review
Adult female mammals are endowed with the unique ability to produce milk for nourishing their newborn offspring. Milk is secreted on demand by the mammary gland, an organ which develops during puberty, further matures during pregnancy and lactation, but reverts to a resting state after weaning. The glandular tissue (re)generated through this series of structural and functional changes is finely sourced by resident stem cells under the control of systemic hormones and local stimuli.Over the past decades a plethora of studies have been carried out in order to identify and characterize mammary stem cells, primarily in mice and humans. Intriguingly, it is now emerging that multiple mammary stem cell pools (co)exist and are characterized by distinctive molecular markers and context-dependent functions.This chapter reviews the heterogeneity of the mammary stem cell compartment with emphasis on the key properties and molecular regulators of distinct stem cell populations in both the mouse and human glands.
Topics: Animals; Cell Differentiation; Female; Humans; Lactation; Mammary Glands, Animal; Mammary Glands, Human; Pregnancy; Stem Cells
PubMed: 31487022
DOI: 10.1007/978-3-030-24108-7_7 -
Science (New York, N.Y.) Oct 2014Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals... (Review)
Review
Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals emanating from the niche can act as self-renewal factors for stem cells in multiple mammalian tissues. Wnt proteins are lipid-modified, which constrains them to act as short-range cellular signals. The locality of Wnt signaling dictates that stem cells exiting the Wnt signaling domain differentiate, spatially delimiting the niche in certain tissues. In some instances, stem cells may act as or generate their own niche, enabling the self-organization of patterned tissues. In this Review, we discuss the various ways by which Wnt operates in stem cell control and, in doing so, identify an integral program for tissue renewal and regeneration.
Topics: Animals; Brain; Cell Division; Hair Follicle; Humans; Intestines; Mammary Glands, Human; Regeneration; Signal Transduction; Stem Cell Niche; Stem Cells; Transcription, Genetic; Wnt Proteins
PubMed: 25278615
DOI: 10.1126/science.1248012 -
Cell Nov 2009Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening...
Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.
Topics: Aging; Animals; Breast Neoplasms; Collagen; Epidermal Growth Factor; Extracellular Matrix; Female; Fibrosis; Genes, ras; Humans; Integrins; Mammary Glands, Human; Mice; Mice, Inbred BALB C; Protein-Lysine 6-Oxidase; Signal Transduction
PubMed: 19931152
DOI: 10.1016/j.cell.2009.10.027 -
Current Topics in Developmental Biology 2014The mammary epithelium undergoes enormous morphogenetic changes during the lifespan of a mammal. The recent elucidation of an epithelial differentiation hierarchy in the... (Review)
Review
The mammary epithelium undergoes enormous morphogenetic changes during the lifespan of a mammal. The recent elucidation of an epithelial differentiation hierarchy in the mouse mammary gland through classical transplantation and clonogenic assays has pointed to the existence of multipotent mammary stem cells (MaSCs) and at least two distinct luminal progenitor types. Moreover, an analogous functional hierarchy has been defined in human breast tissue. The existence of slow cycling stem cells, both long- and short-term repopulating cells, and a unique fetal MaSC population, imply a complex stem cell compartment within the mammary gland. The recent discovery of unipotent stem-like cells from lineage tracing studies has added a further layer of complexity to the emerging differentiation hierarchy. Although the precise relationships between stem and progenitor cells have yet to be resolved, the epithelial hierarchy has provided an important framework for elucidating the roles of molecular regulators of mammary gland ontogeny and understanding potential cells of origin in breast cancer.
Topics: Animals; Cell Lineage; Epithelial Cells; Humans; Mammary Glands, Human; Mice; Models, Biological; Paracrine Communication; RNA, Untranslated; Regulatory Elements, Transcriptional; Species Specificity; Stem Cells; Transcription Factors
PubMed: 24439805
DOI: 10.1016/B978-0-12-416022-4.00005-6 -
Journal of Mammary Gland Biology and... Apr 1998The mammary fat pad is essential for development of the mammary epithelium, providing signals that mediate ductal morphogenesis and, probably, alveolar differentiation.... (Review)
Review
The mammary fat pad is essential for development of the mammary epithelium, providing signals that mediate ductal morphogenesis and, probably, alveolar differentiation. The "cleared" fat pad is often used as a transplantation site. Considering the crucial role of the fat pad, its properties have received relatively little attention from researchers in the field. Some of the questions whose investigation is pertinent to understanding both normal mammary development and carcinogenesis are outlined in this commentary in the spirit of stimulating enquiry into this important subject. It is clear from a brief perusal of the available literature that until studies are specifically designed to clearly differentiate between functional effects of the fibrous and the adipose stroma, more substantive information about their differential effects on mammary development and tumorigenesis will not be forthcoming.
Topics: Adipose Tissue; Animals; Breast; Epithelial Cells; Epithelium; Female; Humans; Mammary Glands, Animal
PubMed: 10819521
DOI: 10.1023/a:1018786604818 -
Seminars in Cell & Developmental Biology Jul 2014The mammary gland is composed of a highly branched network of epithelial tubes, embedded within a complex stroma. The mammary epithelium originates during embryonic... (Review)
Review
The mammary gland is composed of a highly branched network of epithelial tubes, embedded within a complex stroma. The mammary epithelium originates during embryonic development from an epidermal placode. However, the majority of ductal elongation and bifurcation occurs postnatally, in response to steroid hormone and growth factor receptor signaling. The process of pubertal branching morphogenesis involves both elongation of the primary ducts across the length of the fat pad and a wave of secondary branching that elaborates the ductal network. Recent studies have revealed that mammary epithelial morphogenesis is accomplished by transitions between simple and stratified organization. During active morphogenesis, the epithelium is stratified, highly proliferative, has few intercellular junctions, and exhibits incomplete apico-basal polarity. In this review, we discuss recent advances in our understanding of the relationship between epithelial architecture, epithelial polarity, and ductal elongation.
Topics: Animals; Epithelium; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Morphogenesis
PubMed: 24747369
DOI: 10.1016/j.semcdb.2014.04.019 -
Science Translational Medicine Feb 2023Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether...
Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in or is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.
Topics: Female; Humans; Animals; Mice; Germ-Line Mutation; Leptin; Mammary Glands, Human; Phosphatidylinositol 3-Kinases; BRCA2 Protein; BRCA1 Protein; Breast Neoplasms; DNA Damage; Epithelium; Obesity; Estrogens; Mutation; Tumor Microenvironment
PubMed: 36812344
DOI: 10.1126/scitranslmed.ade1857