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The FEBS Journal Jun 2016The RANK signaling pathway has emerged as a new target in breast cancer as receptor activator of nuclear factor κB ligand (RANKL) and its receptor RANK mediate the... (Review)
Review
The RANK signaling pathway has emerged as a new target in breast cancer as receptor activator of nuclear factor κB ligand (RANKL) and its receptor RANK mediate the pro-tumorigenic role of progesterone in the mammary gland. Thousands of cancer patients worldwide are already taking RANKL inhibitors for the management of bone metastasis, given the relevance of this pathway in osteoclastogenesis and bone resorption. RANK signaling also has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses and in the induction of tolerance: it is required for lymph node organogenesis, thymic medullary epithelial development and self-tolerance, and regulates activation of several immune cells and inflammatory processes. The RANK pathway interferes with mammary epithelial differentiation and mediates the major proliferative response of mammary epithelium to progesterone and progesterone-driven expansion of mammary stem cells; it also controls hair follicle and epidermal stem cell homeostasis, pointing to RANK as a key regulator of epithelial stemness. Here we revisit the main functions of RANK signaling in bone remodeling, immune cells and epithelial differentiation. We also discuss the mechanistic evidence that supports its pleiotropic effects on cancer: from bone metastasis to immune and cancer-cell-dependent effects.
Topics: Bone Remodeling; Breast Neoplasms; Cell Differentiation; Epithelial Cells; Female; Humans; Mammary Glands, Human; Molecular Targeted Therapy; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction
PubMed: 26749530
DOI: 10.1111/febs.13645 -
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 -
Molecular and Cellular Endocrinology Jan 2021During puberty, the mammary gland undergoes an intense growth, dependent on the interplay between the Epidermal Growth Factor Receptor (EGFR) in the stroma and different...
During puberty, the mammary gland undergoes an intense growth, dependent on the interplay between the Epidermal Growth Factor Receptor (EGFR) in the stroma and different mammary epithelial receptors. We hypothesize that EGFR expressed in the mammary epithelium also has a role in puberty and the epithelial cells can self-sustain by EGFR-mediated autocrine signaling. We adopted mammary cell lines from different species, as in vitro model for the epithelium, and we observed that EGFR-signaling positively affects their survival and proliferation. Once deprived of external growth factors, mammary cells still showed strong Erk 1/2 phosphorylation, abolished upon EGFR inhibition, coupled with a further reduction in survival and proliferation. Based on gene expression analysis, three EGFR-ligands (AREG, EREG and HBEGF) are likely to mediate this autocrine signaling. In conclusion, internal EGFR-activating signals sustain mammary epithelial cell proliferation and survival in vitro.
Topics: Animals; Autocrine Communication; Cattle; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Epithelial Cells; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Intercellular Signaling Peptides and Proteins; Keratin-14; Keratin-18; Ligands; Mammary Glands, Animal; Mammary Glands, Human; Mice; Receptor, ErbB-2; Signal Transduction; Species Specificity
PubMed: 33181234
DOI: 10.1016/j.mce.2020.111081 -
Cellular and Molecular Life Sciences :... Nov 2014Advances in the study of hematopoietic cell maturation have paved the way to a deeper understanding the stem and progenitor cellular hierarchy in the mammary gland. The... (Review)
Review
Advances in the study of hematopoietic cell maturation have paved the way to a deeper understanding the stem and progenitor cellular hierarchy in the mammary gland. The mammary epithelium, unlike the hematopoietic cellular hierarchy, sits in a complex niche where communication between epithelial cells and signals from the systemic hormonal milieu, as well as from extra-cellular matrix, influence cell fate decisions and contribute to tissue homeostasis. We review the discovery, definition and regulation of the mammary cellular hierarchy and we describe the development of the concepts that have guided our investigations. We outline recent advances in in vivo lineage tracing that is now challenging many of our assumptions regarding the behavior of mammary stem cells, and we show how understanding these cellular lineages has altered our view of breast cancer.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Lineage; Female; Genetic Heterogeneity; Humans; Mammary Glands, Human; Neoplastic Stem Cells; Stem Cells
PubMed: 25080108
DOI: 10.1007/s00018-014-1674-4 -
Molecular Biology of the Cell Oct 2016Integrins are cell surface receptors that bind cells to their physical external environment, linking the extracellular matrix to cell function. They are essential in the... (Review)
Review
Integrins are cell surface receptors that bind cells to their physical external environment, linking the extracellular matrix to cell function. They are essential in the biology of all animals. In the late 1980s, we discovered that integrins are required for the ability of breast epithelia to do what they are programmed to do, which is to differentiate and make milk. Since then, integrins have been shown to control most other aspects of phenotype: to stay alive, to divide, and to move about. Integrins also provide part of the mechanism that allows cells to form tissues. Here I discuss how we discovered that integrins control mammary gland differentiation and explore the role of integrins as central architects of other aspects of cell behavior.
Topics: Animals; Breast; Cell Adhesion; Cell Differentiation; Cell Movement; Epithelium; Extracellular Matrix; Female; Humans; Integrins; Mammary Glands, Human; Receptors, Cell Surface; Signal Transduction
PubMed: 27687254
DOI: 10.1091/mbc.E15-06-0369 -
Breast Cancer Research : BCR Nov 2022Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research...
Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins.
BACKGROUND
Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research aimed at improving clinical strategy for targeted therapeutics.
METHODS
Different combinations of genetic aberrations (Brca1 and Trp53 loss, and inhibition of proteins of the Rb family) were induced in the mammary gland by injection of adenovirus expressing Cre recombinase into the mammary ducts of adult genetically engineered mice. Mammary tumors with different genetic aberrations were classified into molecular subtypes based on expression of molecular markers and RNAseq analysis. In vitro potency assays and Western blots were used to examine their drug sensitivities.
RESULTS
Induction of Brca1 and Trp53 loss in mammary ductal epithelium resulted in development of basal-like hormone receptor (HR)-negative mammary tumors. Inhibition of Rb and Trp53 loss or the combination of Rb, Trp53 and Brca1 aberrations resulted in development of luminal ductal carcinoma positive for ER, PR, and Her2 expression. HR positivity in tumors with Rb, Trp53 and Brca1 aberrations indicated that functionality of the Rb pathway rather than Brca1 status affected HR status in these models. Mammary tumor gene expression profiles recapitulated human basal-like or luminal B breast cancer signatures, but HR-positive luminal cancer models were endocrine resistant and exhibited upregulation of PI3K signaling and sensitivity to this pathway inhibition. Furthermore, both tumor subtypes were resistant to CDK4/6 inhibition.
CONCLUSIONS
Examination of molecular expression profiles and drug sensitivities of tumors indicate that these breast cancer models can be utilized as a translational platform for evaluation of targeted combinations to improve chemotherapeutic response in patients that no longer respond to hormone therapy or that are resistant to CDK4/6 inhibition.
Topics: Mice; Animals; Humans; Female; Mammary Glands, Human; Phosphatidylinositol 3-Kinases; Breast Neoplasms; Mammary Neoplasms, Animal; Epithelium; Hormones; BRCA1 Protein
PubMed: 36333737
DOI: 10.1186/s13058-022-01566-4 -
Hormones & Cancer Apr 2011There is emerging evidence that the mammary epithelium in both mice and humans is arranged as a hierarchy that spans from stem cells to differentiated hormone-sensing,... (Review)
Review
There is emerging evidence that the mammary epithelium in both mice and humans is arranged as a hierarchy that spans from stem cells to differentiated hormone-sensing, milk-producing and myoepithelial cells. It is well established that estrogen is an important mediator of mammary gland morphogenesis and exposure to this hormone is associated with increased breast cancer risk. Yet surprisingly, the primitive cells of the mammary epithelium do not express the estrogen receptor-α (ERα) or the progesterone receptor. This article will review the mammary epithelial cell hierarchy, possible cells of origin of different types of breast tumors, and the potential mechanisms on how estrogen and progesterone may influence the different subcomponents in normal development and in cancer. Also presented are some hypothetical scenarios on how this underlying biology may be reflected in the behavior of ERα(+) and ERα(-) breast tumors.
Topics: Animals; Breast Neoplasms; Estrogens; Female; Humans; Mammary Glands, Human; Progesterone; Receptors, Estrogen; Receptors, Progesterone
PubMed: 21761331
DOI: 10.1007/s12672-010-0055-1 -
Cancer Research Jan 2020Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this...
Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate extracellular matrix (ECM)-directed protrusions, release from the epithelium, and migrate through the ECM. Antibody-based protein profiling revealed that Prkd1 induced broad phosphorylation changes, including an inactivating phosphorylation of β-catenin and two microtubule depolymerizing phosphorylations of Tau, potentially explaining the release of cell-cell contacts and persistent activation of Prkd1. In patients with breast cancer, and expression correlated with metastatic recurrence, particularly in basal breast cancer. Prkd1 knockdown was sufficient to block dissemination of both murine and human mammary tumor organoids. Finally, knockdown blocked primary tumor invasion and distant metastasis in a mouse model of basal breast cancer. Collectively, these data identify Prkd1 as a novel and targetable signaling node downstream of Twist1 that is required for epithelial invasion and dissemination. SIGNIFICANCE: Twist1 is a known regulator of metastatic cell behaviors but not directly targetable. This study provides a molecular explanation for how Twist1-induced dissemination works and demonstrates that it can be targeted. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/2/204/F1.large.jpg.
Topics: Animals; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Datasets as Topic; Epithelial Cells; Epithelial-Mesenchymal Transition; Epithelium; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mammary Neoplasms, Experimental; Mice; Microtubules; Neoplasm Invasiveness; Nuclear Proteins; Primary Cell Culture; Protein Kinase C; RNA-Seq; Signal Transduction; Twist-Related Protein 1
PubMed: 31676574
DOI: 10.1158/0008-5472.CAN-18-3241 -
The International Journal of... 2011Distinct subsets of cells, including cells with stem cell-like properties, have been proposed to exist in normal human breast epithelium and breast carcinomas. The... (Review)
Review
Distinct subsets of cells, including cells with stem cell-like properties, have been proposed to exist in normal human breast epithelium and breast carcinomas. The cellular origins of epithelial cells contributing to gland development, tissue homeostasis and cancer are, however, still poorly understood. The mouse is a widely used model of mammary gland development, both directly by studying the mouse mammary epithelial cells themselves and indirectly, by studying development, morphogenesis, differentiation and carcinogenesis of xenotransplanted human breast epithelium in vivo. While in early studies, human or mouse epithelium was implanted as fragments into the mouse gland, more recent technical progress has allowed the self-renewal capacity and differentiation potential of distinct cell populations or even individual cells to be interrogated. Here, we review and discuss similarities and differences between mouse and human gland development with particular emphasis on the identity and localization of stem cells, and the influence of the surrounding microenvironment. It is concluded that while recent advances in the field have contributed immense insight into how the normal mammary gland develops and is maintained, significant discrepancies exist between the mouse and human gland which should be taken into consideration in current and future models of mammary stem cell biology.
Topics: Animals; Breast; Breast Neoplasms; Cell Differentiation; Cell Lineage; Female; Humans; Mammary Glands, Animal; Mice; Neoplastic Stem Cells; Signal Transduction; Stem Cell Niche; Stem Cell Transplantation; Stem Cells; Transplantation, Heterologous; Tumor Microenvironment
PubMed: 22161829
DOI: 10.1387/ijdb.113373af -
Cell Reports Jan 2024Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary...
Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically, PAPAS transcription depends on R-loop formation at the 3' end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.
Topics: Pregnancy; Female; Mice; Animals; Humans; Mammary Glands, Animal; Breast; Cell Differentiation; Breast Neoplasms; Cell Transformation, Neoplastic; Epithelial Cells
PubMed: 38180837
DOI: 10.1016/j.celrep.2023.113644