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"Mammary glands"
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Milk : the biology of lactation
\"After drawing its first breath, every newborn mammal turns his or her complete attention to obtaining milk. This primal act was once thought to stem from a basic fact: milk provides the initial source of calories and nutrients for all mammalian young. But it turns out that milk is a much more complicated biochemical cocktail and provides benefits beyond nutrition. In this fascinating book, biologists Michael L. Power and Jay Schulkin reveal this liquid's evolutionary history and show how its ingredients have changed over many millions of years to become a potent elixir. Power and Schulkin walk readers through the early origins of the mammary gland and describe the incredible diversification of milk among the various mammalian lineages. After revealing the roots of lactation, the authors describe the substances that naturally occur in milk and discuss their biological functions. They reveal that mothers pass along numerous biochemical signals to their babies through milk. The authors explain how milk boosts an infant's immune system, affects an infant's metabolism and physiology, and helps inoculate and feed the baby's gut microbiome. Throughout the book, the authors weave in stories from studies of other species, explaining how comparative research sheds light on human lactation. The authors then turn their attention to the fascinating topic of cross-species milk consumption--something only practiced by certain humans who evolved an ability to retain lactase synthesis into adulthood. The first book to discuss milk from a comparative and evolutionary perspective, Power and Schulkin's masterpiece reveals the rich biological story of the common thread that connects all mammals\"-- Provided by publisher.
Book
CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis
Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4
+
macrophages as a niche population enriched in normal mammary ducts, where they promote the regenerative activity of basal cells in response to luminal cell-derived CXCL12. CXCL12 triggers AKT-mediated stabilization of β-catenin, which induces Wnt ligands and pro-migratory genes, enabling intraductal macrophage infiltration and supporting regenerative activity of basal cells. Notably, these same CXCR4
+
niche macrophages regulate the tumor-initiating activity of various breast cancer subtypes by enhancing TIC survival and tumor-forming capacity, while promoting early immune evasion through regulatory T cell induction. Furthermore, a CXCR4
+
niche macrophage gene signature correlates with poor prognosis in human breast cancer. These findings highlight the pivotal role of the CXCL12-CXCR4 axis in orchestrating interactions between niche macrophages, mammary epithelial cells, and immune cells, thereby establishing a supportive niche for both normal tissue regeneration and mammary tumor initiation.
Mammary gland resident macrophages are known to be crucial components of the mammary stem cell niche. Here, the authors show that CXCR4
+
macrophages form a niche that regulates the tumor-initiating activity of breast cancer cells and induces early immune evasion through the recruitment of regulatory T cells.
Journal Article
Immune Cell Contribution to Mammary Gland Development
Postpartum breast cancer (PPBC) is a unique subset of breast cancer, accounting for nearly half of the women diagnosed during their postpartum years. Mammary gland involution is widely regarded as being a key orchestrator in the initiation and progression of PPBC due to its unique wound-healing inflammatory signature. Here, we provide dialogue suggestive that lactation may also facilitate neoplastic development as a result of sterile inflammation. Immune cells are involved in all stages of postnatal mammary development. It has been proposed that the functions of these immune cells are partially directed by mammary epithelial cells (MECs) and the cytokines they produce. This suggests that a more niche area of exploration aimed at assessing activation of innate immune pathways within MECs could provide insight into immune cell contributions to the developing mammary gland. Immune cell contribution to pubertal development and mammary gland involution has been extensively studied; however, investigations into pregnancy and lactation remain limited. During pregnancy, the mammary gland undergoes dramatic expansion to prepare for lactation. As a result, MECs are susceptible to replicative stress. During lactation, mitochondria are pushed to capacity to fulfill the high energetic demands of producing milk. This replicative and metabolic stress, if unresolved, can elicit activation of innate immune pathways within differentiating MECs. In this review, we broadly discuss postnatal mammary development and current knowledge of immune cell contribution to each developmental stage, while also emphasizing a more unique area of study that will be beneficial in the discovery of novel therapeutic biomarkers of PPBC.
Journal Article
Multiscale imaging of basal cell dynamics in the functionally mature mammary gland
The mammary epithelium is indispensable for the continued survival of more than 5,000 mammalian species. For some, the volume of milk ejected in a single day exceeds their entire blood volume. Here, we unveil the spatiotemporal properties of physiological signals that orchestrate the ejection of milk from alveolar units and its passage along the mammary ductal network. Using quantitative, multidimensional imaging of mammary cell ensembles from GCaMP6 transgenic mice, we reveal how stimulus evoked Ca2+ oscillations couple to contractions in basal epithelial cells. Moreover, we show that Ca2+-dependent contractions generate the requisite force to physically deform the innermost layer of luminal cells, compelling them to discharge the fluid that they produced and housed. Through the collective action of thousands of these biological positive-displacement pumps, each linked to a contractile ductal network, milk begins its passage toward the dependent neonate, seconds after the command.
Journal Article
Developmental Regulation of circRNAs in Normal and Diseased Mammary Gland: A Focus on circRNA-miRNA Networks
Circular RNAs (circRNAs) have emerged as critical regulators in various biological processes including diseases. In the mammary gland (MG), which undergoes most of its development postnatally, circRNAs play pivotal roles in both physiological and pathological contexts. This review highlights the involvement of circRNAs during key developmental stages of the MG, with particular emphasis on lactation, where circRNA-miRNA networks significantly influence milk secretion and composition. CircRNAs exhibit stage-, breed- and species-specific expression patterns during lactation, which underscores their complexity. This intricate regulation also plays a significant role in pathological conditions of the MG, where dysregulated circRNA expression contributes to disease progression such as mastitis, early breast cancer (BC) stages, and epithelial-to-mesenchymal transition in BC (EMT). In mastitis, altered circRNA expression disrupts immune responses and compromises epithelial integrity. During early BC progression, circRNAs drive cell proliferation, while in EMT, they facilitate metastatic processes. By focusing on the circRNA-miRNA interactions underlying these processes, this review highlights their potential use as biomarkers for MG development, disease progression, and as therapeutic targets.
Journal Article
Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression
From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer.
Journal Article
Distinct stem cells contribute to mammary gland development and maintenance
The mammary epithelium is composed of several cell lineages including luminal, alveolar and myoepithelial cells. Transplantation studies have suggested that the mammary epithelium is maintained by the presence of multipotent mammary stem cells. To define the cellular hierarchy of the mammary gland during physiological conditions, we performed genetic lineage-tracing experiments and clonal analysis of the mouse mammary gland during development, adulthood and pregnancy. We found that in postnatal unperturbed mammary gland, both luminal and myoepithelial lineages contain long-lived unipotent stem cells that display extensive renewing capacities, as demonstrated by their ability to clonally expand during morphogenesis and adult life as well as undergo massive expansion during several cycles of pregnancy. The demonstration that the mammary gland contains different types of long-lived stem cells has profound implications for our understanding of mammary gland physiology and will be instrumental in unravelling the cells at the origin of breast cancers.
Mammary stem cells
Using lineage-tracing approaches in mice, Cédric Blanpain and colleagues decipher the cellular hierarchy of the mammary epithelium during development, homeostasis and lactation. They find that the various cell lineages of mammary epithelium originate from and are maintained by different classes of unipotent stem cells rather than by multipotent stem cells, as was previously thought. As well as having implications for our understanding of mammary gland physiology, this finding is of relevance to attempts to identify the cells at the origin of breast cancers.
Journal Article
Stromal PTEN determines mammary epithelial response to radiotherapy
The importance of the tumor–associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (
Pten
) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.
The tumor microenvironment influences tumor progression. Here the authors show that lack of stromal PTEN phosphatase induces DNA repair defects in the neighboring mammary gland epithelial cells via hyperactivation of EGF-receptor signaling, resulting in higher radiation-induced DNA damage and hyperplasia.
Journal Article
The Role of Tight Junctions in Mammary Gland Function
Tight junctions (TJ) are cellular structures that facilitate cell-cell communication and are important in maintaining the three-dimensional structure of epithelia. It is only during the last two decades that the molecular make-up of TJ is becoming unravelled, with two major transmembrane-spanning structural protein families, called occludin and claudins, being the true constituents of the TJ. These TJ proteins are linked via specific scaffolding proteins to the cell’s cytoskeleton. In the mammary gland TJ between adjacent secretory epithelial cells are formed during lactogenesis and are instrumental in establishing and maintaining milk synthesis and secretion, whereas TJ integrity is compromised during mammary involution and also as result of mastitis and periods of mammary inflamation (including mastitis). They prevent the paracellular transport of ions and small molecules between the blood and milk compartments. Formation of intact TJ at the start of lactation is important for the establishment of the lactation. Conversely, loss of TJ integrity has been linked to reduced milk secretion and mammary function and increased paracellular transport of blood components into the milk and vice versa. In addition to acting as a paracellular barrier, the TJ is increasingly linked to playing an active role in intracellular signalling. This review focusses on the role of TJ in mammary function of the normal, non-malignant mammary gland, predominantly in ruminants, the major dairy producing species.
Journal Article
ErbB/EGF Signaling and EMT in Mammary Development and Breast Cancer
Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling pathways that control proliferation, survival, angiogenesis and metastasis of breast cancer. In this respect, clinical trials with various ErbB receptor blocking antibodies and specific tyrosine kinase inhibitors have proven to be partially efficacious in the treatment of this heterogeneous disease. Induction of an embryonic program of epithelial-to-mesenchymal transition (EMT) in breast cancer, whereupon epithelial tumor cells convert to a more mesenchymal-like phenotype, facilitates the migration, intravasation, and extravasation of tumor cells during metastasis. Breast cancers which exhibit properties of EMT are highly aggressive and resistant to therapy. Activation of ErbB signaling can regulate EMT-associated invasion and migration in normal and malignant mammary epithelial cells, as well as modulating discrete stages of mammary gland development. The purpose of this review is to summarize current information regarding the role of ErbB signaling in aspects of EMT that influence epithelial cell plasticity during mammary gland development and tumorigenesis. How this information may contribute to the improvement of therapeutic approaches in breast cancer will also be addressed.
Journal Article