-
Cellular and Molecular Life Sciences :... Dec 2007During its lifetime, the mammary gland undergoes many phases of development and differentiation. Much of this occurs during puberty, when the ductal epithelium expands... (Review)
Review
During its lifetime, the mammary gland undergoes many phases of development and differentiation. Much of this occurs during puberty, when the ductal epithelium expands by branching morphogenesis, invading the surrounding fat pad to form an organised mammary tree. Throughout its existence, the epithelium will go through several cycles of proliferation and cell death during pregnancy, lactation and involution. Many of the signalling mechanisms which control the initial invasion of the fat pad by the epithelium, and regulate its continuing plasticity, can be harnessed or corrupted by tumour cells in order to support their aberrant growth and progression towards invasion. This is true not just for the epithelial cells themselves but also for cells in the surrounding microenvironment, including fibroblasts, macrophages and adipocytes. This review examines the complex web of signalling and adhesion interactions controlling branching morphogenesis, and how their alteration can promote malignancy. Current in vivo and in vitro mammary gland models are also discussed. (Part of a Multi-author Review).
Topics: Animals; Breast Neoplasms; Cell Adhesion; Epidermal Growth Factor; Humans; Mammary Glands, Animal; Mammary Glands, Human; Matrix Metalloproteinases; Models, Biological; Neoplasm Invasiveness; Oncogene Proteins v-erbB; Stem Cells; Transcription Factors; Transforming Growth Factor beta
PubMed: 17955178
DOI: 10.1007/s00018-007-7386-2 -
Seminars in Cell & Developmental Biology Feb 2010It is increasingly apparent that normal and malignant breast tissues require complex local and systemic stromal interactions for development and progression. During... (Review)
Review
It is increasingly apparent that normal and malignant breast tissues require complex local and systemic stromal interactions for development and progression. During development, mammary cell fate specification and differentiation require highly regulated contextual signals derived from the stroma. Likewise, during breast carcinoma development, the tissue stroma can provide tumor suppressing and tumor-promoting environments that serve to regulate neoplastic growth of the epithelium. This review focuses on the role of the stroma as a mediator of normal mammary development, as well as a critical regulator of malignant conversion and progression in breast cancer. Recognition of the important role of the stroma during the progression of breast cancers leads to the possibility of new targets for treatment of the initial breast cancer lesion as well as prevention of recurrence.
Topics: Animals; Breast; Breast Neoplasms; Cell Transformation, Neoplastic; Connective Tissue; Disease Progression; Female; Fibrosis; Humans; Stromal Cells
PubMed: 19857593
DOI: 10.1016/j.semcdb.2009.10.003 -
Cell Reports Jul 2019DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but...
DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell activity, including luminobasal differentiation, and are protected from mammary cancer, we reasoned that Slug might regulate DNA damage checkpoints in mammary epithelial cells. Here, we show that Slug facilitates efficient execution of RPA32-mediated DNA damage response (DDR) signaling. Slug deficiency leads to delayed phosphorylation of ataxia telangiectasia mutated and Rad3-related protein (ATR) and its effectors RPA32 and CHK1. This leads to impaired RAD51 recruitment to DNA damage sites and persistence of unresolved DNA damage. In vivo, Slug/Snai2 loss leads to increased DNA damage and premature aging of mammary epithelium. Collectively, our work demonstrates that the mammary stem cell regulator Slug controls DDR checkpoints by dually inhibiting differentiation and facilitating DDR repair, and its loss causes unresolved DNA damage and accelerated aging.
Topics: Animals; Cell Differentiation; Cell Line; Cell Line, Tumor; Cellular Senescence; DNA Damage; DNA Repair; HEK293 Cells; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Mice, Inbred NOD; Mice, SCID; Snail Family Transcription Factors
PubMed: 31291576
DOI: 10.1016/j.celrep.2019.06.043 -
Current Topics in Developmental Biology 2015Epithelial tissues are essential for barrier function, secretion, and regulation of fluid transport. Their function requires cell polarity and cell-cell adhesion,... (Review)
Review
Epithelial tissues are essential for barrier function, secretion, and regulation of fluid transport. Their function requires cell polarity and cell-cell adhesion, mediated through intercellular junctions. Conversely, disruption of adhesion and polarity is thought to drive cancer progression. The mammary gland is an important model for cell adhesion due to its postnatal hormonally regulated development; ducts undergo branching morphogenesis in response to steroid hormones during puberty. These hormonal signals induce a transition from simple to stratified architecture, initiated by asymmetric luminal cell divisions. Ductal elongation is accomplished by this multilayered, low-polarity epithelium, and polarity is reestablished as elongation ceases. The requirement for cell adhesion has been tested in 3D culture and in vivo, using gene deletion, knockdown, and misexpression in both developmental and homeostatic contexts. Attention has focused on E-cadherin, the major classical cadherin in luminal epithelial cells. Classic studies revealed a requirement for E-cadherin during lactation, and E-cadherin loss is widely posited to promote metastasis. However, recent findings demonstrated a broader requirement for E-cadherin during branching morphogenesis and homeostasis and also, surprisingly, in epithelial dissemination. These studies suggest that long-standing models of the role of adhesion in epithelial biology need to be revisited. Advances in inducible gene expression and knockdown, CRISPR/Cas9 technology, and fluorescent labeling of genetically modified cells offer the opportunity to test the roles of diverse adhesion systems and to develop a mechanistic understanding of how cell adhesion regulates development and cancer.
Topics: Animals; Cadherins; Cell Adhesion; Cell Movement; Humans; Mammary Glands, Human; Organogenesis; Signal Transduction
PubMed: 25733146
DOI: 10.1016/bs.ctdb.2014.12.001 -
Biomaterials Apr 2019The intricate architecture of branched tissues and organs has fascinated scientists and engineers for centuries. Yet-despite their ubiquity-the biophysical and... (Review)
Review
The intricate architecture of branched tissues and organs has fascinated scientists and engineers for centuries. Yet-despite their ubiquity-the biophysical and biochemical mechanisms by which tissues and organs undergo branching morphogenesis remain unclear. With the advent of three-dimensional (3D) culture models, an increasingly powerful and diverse set of tools are available for investigating the development and remodeling of branched tissues and organs. In this review, we discuss the application of 3D culture models for studying branching morphogenesis of the mammary gland and the mammalian lung in the context of normal development and disease. While current 3D culture models lack the cellular and molecular complexity observed in vivo, we emphasize how these models can be used to answer targeted questions about branching morphogenesis. We highlight the specific advantages and limitations of using 3D culture models to study the dynamics and mechanisms of branching in the mammary gland and mammalian lung. Finally, we discuss potential directions for future research and propose strategies for engineering the next generation of 3D culture models for studying tissue morphogenesis.
Topics: Animals; Equipment Design; Humans; Lab-On-A-Chip Devices; Lung; Mammary Glands, Human; Morphogenesis; Organ Culture Techniques; Organoids; Tissue Engineering
PubMed: 30174198
DOI: 10.1016/j.biomaterials.2018.08.043 -
The FEBS Journal Jan 2020The adult mammary gland undergoes dynamic changes during puberty and the postnatal developmental cycle. The mammary epithelium is composed of a bilayer of outer basal,...
The adult mammary gland undergoes dynamic changes during puberty and the postnatal developmental cycle. The mammary epithelium is composed of a bilayer of outer basal, or myoepithelial, cells and inner luminal cells, the latter lineage giving rise to the milk-producing alveolar cells during pregnancy. These luminal alveolar cells undergo Stat3-mediated programmed cell death following the cessation of lactation. It is established that immune cells in the microenvironment of the gland have a role to play both in the ductal outgrowth during puberty and in the removal of dead cells and remodelling of the stroma during the process of postlactational regression. However, most studies have focussed on the role of the stromal immune cell compartment or have quantified immune cell populations in tissue extracts. Our recent development of protocols for deep imaging of the mammary gland in three dimensions (3D) has enabled the architectural relationship between immune cells and the epithelium to be examined in detail, and we have discovered a surprisingly dynamic relationship between the basal epithelium and leucocytes. Furthermore, we have observed morphological changes in the myoepithelial cells, as involution progresses, which were not revealed by previous work in 2D tissue sections and whole tissue. This dynamic architecture suggests a role for myoepithelial cells in the orderly progression of involution. We conclude that deep imaging of mammary gland and other tissues is essential for analysing complex interactions between cellular compartments.
Topics: Animals; Epithelial Cells; Female; Humans; Lactation; Leukocytes; Mammary Glands, Human; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 31691481
DOI: 10.1111/febs.15126 -
Breast Cancer Research : BCR 2006The mammary epithelium contains multipotent stem cells that give rise to all differentiated cell types present within the tissue. Mammary epithelial stem cells have been... (Review)
Review
The mammary epithelium contains multipotent stem cells that give rise to all differentiated cell types present within the tissue. Mammary epithelial stem cells have been prospectively purified from dissociated mammary epithelium on the basis of cell surface antigen expression. It has become apparent in recent years that for breast cancer and other malignancies only a small proportion of tumour cells--'cancer stem cells'--have the capacity for extensive proliferation and transferral of the tumour. We review the evidence for breast cancer stem cells, we consider their relationship to mammary epithelial stem cells and we examine the implications for current and future therapeutic strategies.
Topics: Breast; Breast Neoplasms; Cell Proliferation; Epithelial Cells; Female; Humans; Stem Cell Transplantation
PubMed: 16834766
DOI: 10.1186/bcr1513 -
PloS One 2012Loss of epithelial polarity is described as a hallmark of epithelial cancer. To determine the role of Hugl1 and Hugl2 expression in the breast, we investigated their... (Comparative Study)
Comparative Study
Loss of epithelial polarity is described as a hallmark of epithelial cancer. To determine the role of Hugl1 and Hugl2 expression in the breast, we investigated their localization in human mammary duct tissue and the effects of expression modulation in normal and cancer cell lines on polarity, proliferation and differentiation. Expression of Hugl1 and Hugl2 was silenced in both MCF10A cells and Human Mammary Epithelial Cells and cell lines were grown in 2-D on plastic and in 3-D in Matrigel to form acini. Cells in monolayer were compared for proliferative and phenotypic changes while acini were examined for differences in size, ability to form a hollow lumen, nuclear size and shape, and localization of key domain-specific proteins as a measure of polarity. We detected overlapping but distinct localization of Hugl1 and Hugl2 in the human mammary gland, with Hugl1 expressed in both luminal and myoepithelium and Hugl2 largely restricted to myoepithelium. On a plastic surface, loss of Hugl1 or Hugl2 in normal epithelium induced a mesenchymal phenotype, and these cells formed large cellular masses when grown in Matrigel. In addition, loss of Hugl1 or Hugl2 expression in MCF10A cells resulted in increased proliferation on Matrigel, while gain of Hugl1 expression in tumor cells suppressed proliferation. Loss of polarity was also observed with knockdown of either Hugl1 or Hugl2, with cells growing in Matrigel appearing as a multilayered epithelium, with randomly oriented Golgi and multiple enlarged nuclei. Furthermore, Hugl1 knock down resulted in a loss of membrane identity and the development of cellular asymmetries in Human Mammary Epithelial Cells. Overall, these data demonstrate an essential role for both Hugl1 and Hugl2 in the maintenance of breast epithelial polarity and differentiated cell morphology, as well as growth control.
Topics: Blotting, Western; Cell Differentiation; Cell Line, Tumor; Cell Polarity; Cell Proliferation; Collagen; Cytoskeletal Proteins; Drug Combinations; Epithelial Cells; Female; Fluorescent Antibody Technique; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Image Processing, Computer-Assisted; Laminin; Mammary Glands, Human; Microscopy, Fluorescence; Proteoglycans; Tetrazolium Salts; Thiazoles
PubMed: 23110097
DOI: 10.1371/journal.pone.0047734 -
Breast Cancer Research : BCR 2010The protein serine/threonine kinase Akt, also known as protein kinase B (PKB), is arguably the most important signalling nexus in the cell. Akt integrates a plethora of... (Review)
Review
The protein serine/threonine kinase Akt, also known as protein kinase B (PKB), is arguably the most important signalling nexus in the cell. Akt integrates a plethora of extracellular signals to generate diverse outcomes, including proliferation, motility, growth, glucose homeostasis, survival, and cell death. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is the second most frequently mutated pathway in cancer, after p53, and mutations in components of this pathway are found in around 70% of breast cancers. Thus, understanding how Akt relays input signals to downstream effectors is critically important for the design of therapeutic strategies to combat breast cancer. In this review, we will discuss the various signals upstream of Akt that impact on its activity, how Akt integrates these signals and modulates the activity of downstream targets to control mammary gland development, and how mutations in components of the pathway result in breast cancer.
Topics: Breast Neoplasms; Epithelium; Female; Humans; Mammary Glands, Human; Models, Biological; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 20398329
DOI: 10.1186/bcr2558 -
Yakugaku Zasshi : Journal of the... 2018Intrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many... (Review)
Review
Intrinsic serotonin (5-hydroxytryptamine; 5-HT) synthesized within the mammary epithelium has an important physiological role in milk volume homeostasis in many species including mice, cows, and humans. During lactation, mammary epithelial cells activate 5-HT synthesis by tryptophan hydroxylase 1 (TPH1). TPH1 catalyzes the rate-limiting step in 5-HT biosynthesis within mammary glands. 5-HT synthesized in mammary glands is released into both the apical (milk) and basolateral spaces by a vesicular monoamine transporter. 5-HT released into milk is incorporated by the apical membrane-expressed serotonin reuptake transporter and degraded by the monoamine oxidase A enzyme. Suckling maintains 5-HT at low levels in milk. When the mammary gland becomes filled with milk, 5-HT provides a negative feedback signal that suppresses further milk synthesis in the mammary epithelium. Our research, using human mammary epithelial MCF-12A cells, shows that the expression of β-casein, a differentiation marker, is suppressed via 5-HT-mediated inhibition of signal transducer and activator of transcription 5. Additionally, our results show that reduced β-casein expression in MCF-12A cells is associated with 5-HT receptor expression. Furthermore, we show that 5-HT receptor-mediated suppression of β-casein expression is involved in the activation of protein kinase A and protein-tyrosine phosphatase 1B. Thus, this mechanism might be associated with the feedback signals by 5-HT within the mammary epithelium. Hence, further research that builds on our findings should include the elucidation of the physiological roles of 5-HT present in milk synthesized by mammary epithelial cells in vivo and its effects on nursing infants.
Topics: Animals; Caseins; Female; Homeostasis; Humans; Lactation; Mammary Glands, Animal; Mammary Glands, Human; Monoamine Oxidase; Receptors, Serotonin; Serotonin; Tryptophan Hydroxylase
PubMed: 29863055
DOI: 10.1248/yakushi.18-00003