Showing papers in "Journal of Mammary Gland Biology and Neoplasia in 2005"
TL;DR: Tumor cells, osteoblasts, osteoclasts and bone matrix are the four components of a vicious cycle necessary for the initiation and development of bone metastases and their roles in fueling the vicious cycle may identify novel targets for therapies to prevent metastasis.
Abstract: The most common skeletal complication of breast cancer is osteolytic bone metastasis. Bone metastases are present in 80% of patients with advanced disease and cause significant morbidity. They are most often osteolytic, but can be osteoblastic or mixed. Tumor cells, osteoblasts, osteoclasts and bone matrix are the four components of a vicious cycle necessary for the initiation and development of bone metastases. Tumor cell gene expression is modified by interaction with bone-derived factors. For example, parathyroid hormone related protein (PTHrP), a tumor cell factor, is upregulated by bone-derived transforming growth factor β (TGFβ). Tumor cell factors, in turn, act upon bone cells to cause dysregulated bone destruction and formation. PTHrP increases osteoblast expression of RANK (receptor activator of NFκB) ligand which, in turn, activates osteoclasts. PTHrP-independent osteolytic factors, such as interleukin [IL]-11 and IL-8, also contribute to the vicious cycle. Other tumor-bone interactions, such as stimulation of tumor-homing through the CXCR4 chemokine receptor by its bone-derived ligand stromal-derived factor-1 (SDF-1), may be responsible for the site-specific predilection of breast cancer for bone. These factors and their roles in fueling the vicious cycle may identify novel targets for therapies to prevent metastasis.
329 citations
TL;DR: Data from the laboratories and from others regarding the cellular origin of human myoepithelial cells, their function in maintaining tissue polarity in the normal breast, and their role during neoplasia are discussed.
Abstract: The human breast epithelium is a branching ductal system composed of an inner layer of polarized luminal epithelial cells and an outer layer of myoepithelial cells that terminate in distally located terminal duct lobular units (TDLUs). While the luminal epithelial cell has received the most attention as the functionally active milk-producing cell and as the most likely target cell for carcinogenesis, attention on myoepithelial cells has begun to evolve with the recognition that these cells play an active part in branching morphogenesis and tumor suppression. A major question that has been the subject of investigation pertains to how the luminal epithelial and myoepithelial lineages are related and precisely how they arise from a common putative stem cell population within the breast. Equally important is the question of how heterotypic signaling occurs between luminal epithelial and surrounding myoepithelial cells in normal breast morphogenesis and neoplasia. In this review we discuss data from our laboratories and from others regarding the cellular origin of human myoepithelial cells, their function in maintaining tissue polarity in the normal breast, and their role during neoplasia.
277 citations
TL;DR: The development of in vitro suspension culture systems not only provides an important new tool for the study of mammary cell biology, but also may have important implications for understanding key molecular pathways in both normal and neoplastic stem cells.
Abstract: There is increasing evidence that a variety of neoplasms including breast cancer may result from transformation of normal stem and progenitor cells. In the past, isolation and characterization of mammary stem cells has been limited by the lack of suitable culture systems able to maintain these cells in an undifferentiated state in vitro. We have recently described a culture system in which human mammary stem and progenitor cells are able to survive in suspension and produce spherical colonies composed of both stem and progenitor cells. Recent observation that adult stem cells from other tissues may also retain the capacity for growth under anchorage independent conditions suggests a common underlying mechanism. We propose that this mechanism involves the interaction between the canonical Wnt signal pathway and E-cadherin. The Wnt pathway has been implicated in normal stem cell self-renewal in vivo. Furthermore, there is evidence that deregulation of this pathway in the mammary gland and other organs may play a key role in carcinogenesis. Thus, the development of in vitro suspension culture systems not only provides an important new tool for the study of mammary cell biology, but also may have important implications for understanding key molecular pathways in both normal and neoplastic stem cells.
198 citations
TL;DR: The present understanding of the adaptations in mineral metabolism that occur during pregnancy and lactation are reviewed, and recent evidence that the breast itself plays a central role in regulating the adaptations during lactation is focused on.
Abstract: Pregnancy and lactation both place significant demands on the mother to provide sufficient calcium (among other minerals and nutrients) to the fetus and neonate. Despite facing similar demands for calcium during pregnancy and lactation, the maternal adaptations differ significantly between these two reproductive periods. Women lose 300 to 400 mg of calcium daily through breast milk, and this calcium demand is met by a 5–10% loss of skeletal mineral content during 6 months of exclusive lactation. Most importantly, the lost mineral is fully restored within a few months of weaning, such that women who have breastfed do not have a long-term deficit in skeletal mineral content. This article will review our present understanding of the adaptations in mineral metabolism that occur during pregnancy and lactation, and will focus on recent evidence that the breast itself plays a central role in regulating the adaptations during lactation.
188 citations
TL;DR: The role of mammary myoepithelial cells in the progression of breast cancer has been investigated in this paper, showing that they play a key role in breast tumor progression by regulating the in situ to invasive carcinoma transition and are part of the mammary stem cell niche.
Abstract: Mammary myoepithelial cells have been a neglected facet of breast cancer biology, largely ignored since they have been considered to be less important for tumorigenesis than luminal epithelial cells from which most of breast carcinomas are thought to arise. In recent years as our knowledge of stem cell biology and the cellular microenvironment has been increasing, myoepithelial cells are slowly starting to gain more attention. Emerging data raise the hypothesis whether myoepithelial cells play a key role in breast tumor progression by regulating the in situ to invasive carcinoma transition and that myoepithelial cells are part of the mammary stem cell niche. Paracrine interactions between myoepithelial and luminal epithelial cells are known to be important for regulation of cell cycle progression, establishing epithelial cell polarity, and inhibiting cell migration and invasion. Based on these functions, normal mammary myoepithelial cells have been called "natural tumor suppressors." However, during tumor progression myoepithelial cells seem to loose these properties, and eventually this cell population diminishes as tumors become invasive. Better understanding of myoepithelial cell function and their role in tumor progression may lead to their exploitation for cancer therapeutic and preventative measures.
173 citations
TL;DR: A model in which the commitment to the luminal versus the myoepithelial lineage may play a determining role in the generation of alveoli and ducts is proposed.
Abstract: The human mammary gland is organized developmentally as a hierarchy of progenitor cells that become progressively restricted in their proliferative abilities and lineage options. Three types of human mammary epithelial cell progenitors are now identified. The first is thought to be a luminal-restricted progenitor; in vitro under conditions that support both luminal and myoepithelial cell differentiation, this cell produces clones of differentiating daughter cells that are exclusively positive for markers characteristic of luminal cells produced in vivo (i.e., keratins 8/18 and 19, epithelial cell adhesion molecule [EpCAM] and MUC1). The second type is a bipotent progenitor. It is identified by its ability to produce "mixed" colonies in single cell assays. These colonies contain a central core of cells expressing luminal markers surrounded by cells with a morphology and markers (e.g., keratin 14(+)) characteristic of myoepithelial cells. Serial passage in vitro of an enriched population of bipotent progenitors promotes the expansion of a third type of progenitor that is thought to be myoepithelial-restricted because it only produces cells with myoepithelial features. Luminal-restricted and bipotent progenitors can prospectively be isolated as distinct subpopulations from freshly dissociated suspensions of normal human mammary cells. Both are distinguished from many other cell types in mammary tissue by their expression of EpCAM and CD49f (alpha6 integrin). They are distinguished from each other by their differential expression of MUC1, which is expressed at much higher levels on the luminal progenitors. To relate the role of these progenitors to the generation of the three-dimensional tubuloalveolar structure of the mammary tree produced in vivo, we propose a model in which the commitment to the luminal versus the myoepithelial lineage may play a determining role in the generation of alveoli and ducts.
168 citations
TL;DR: This work reviews the literature examining the biological effects of HA crystals in breast cancer cell lines, specifically the mechanism of HA-induced mitogenesis and upregulation of gene expression and concludes that these crystals are associated with both benign and malignant breast tumors.
Abstract: Radiographic mammary calcifications occur in 30-50% of breast cancers and constitute one of the most important diagnostic markers of both benign and malignant lesions of the breast. The presence of oxalate-type microcalcification appears to be a reliable criterion in favor of the benign nature of the lesion or, at most, of a lobular carcinoma in situ. In contrast, calcium hydroxyapatite (HA) crystals are associated with both benign and malignant breast tumors. Although the diagnostic value of microcalcifications in breast cancer is of great importance, the genesis of these calcifications is unclear. Despite numerous histological ultrastructure studies of HA deposits in breast carcinomas, to date there have been limited investigations of the potential role of these crystals in breast cancer. We review the literature examining the biological effects of HA crystals in breast cancer cell lines, specifically the mechanism of HA-induced mitogenesis and upregulation of gene expression.
151 citations
TL;DR: A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.
Abstract: Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumour cells. Copper chelation decreases the secretion of many of these factors. Serum copper levels are upregulated in many human tumours and correlate with tumour burden and prognosis. Copper chelators reduce tumour growth and microvascular density in animal models. New orally active copper chelators have enabled clinical trials to be undertaken, and there are several studies ongoing. A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.
144 citations
TL;DR: The gene expression profile of myoepithelial cells may explain the pronounced anti-invasive and anti-angiogenic effects of the myoepsinhelial cells on carcinoma cells and may also account for the reduced malignancy of myOEPithelial tumors, which are devoid of appreciable angiogenesis and invasive behavior.
Abstract: Host cellular paracrine regulation of tumor progression is an important determinant of tumor biology but one cell that has been ignored in this regulation is the myoepithelial cell. Myoepithelial cells surround normal ducts and precancerous lesions, especially of the breast and form a natural border separating proliferating epithelial cells from proliferating endothelial cells (angiogenesis). Myoepithelial cells may thus negatively regulate tumor invasion and metastasis. Whereas epithelial cells are susceptible targets for transforming events, myoepithelial cells are resistant. Therefore, it can be said that myoepithelial cells function as both autocrine as well as paracrine tumor suppressors. Our laboratory has found that myoepithelial cells secrete a number of suppressor molecules including high amounts of diverse proteinase inhibitors and angiogenic inhibitors but low amounts of proteinases and angiogenic factors compared to common malignant cell lines. This observation has been made in vitro, in mice, and in humans and suggests that myoepithelial cells exert pleiotropic suppressive effects on tumor progression. The gene expression profile of myoepithelial cells may explain the pronounced anti-invasive and anti-angiogenic effects of myoepithelial cells on carcinoma cells and may also account for the reduced malignancy of myoepithelial tumors, which are devoid of appreciable angiogenesis and invasive behavior.
123 citations
TL;DR: Some of the current concepts related to the causes and prevention of milk fever in dairy cattle are highlighted, as well as contrasting differences in calcium demands that exist between dairy cattle, humans and rats at the onset of lactation.
Abstract: Adequate blood calcium concentrations are vital for the normal function of mammals. Mechanisms for maintaining normal blood calcium function adequately most of the time; however, occasionally they fail and calcium homeostasis is compromised. Milk fever or periparturient hypocalcemia in dairy cattle is a well-documented example of a breakdown in the mechanisms of calcium homeostasis. This disease occurs at the time of parturition and is unique to adult dairy animals. The disease results from the inability of animals to cope with the sudden demand for calcium in support of colostrum formation. Animals developing the disease become hypocalcemic and require intravenous calcium to survive. The precise metabolic disorder(s) responsible for the onset of milk fever is still being debated. This report will highlight some of the current concepts related to the causes and prevention of milk fever in dairy cattle, as well as contrasting differences in calcium demands that exist between dairy cattle, humans and rats at the onset of lactation.
120 citations
TL;DR: Evidence that the Side Population of Hematopoietic Stem Cells is enriched for stem cells is, at the moment, only correlative, and there are potentially confounding technical issues.
Abstract: Hematopoietic Stem Cells have been isolated by their ability to pump out Hoechst 33342 dye and form a distinct population definable by flow cytometry—the Side Population (SP). The membrane pump Bcrp has been identified as the molecular determinant of the SP phenotype. An SP population with Bcrp activity has been defined in a number of tissues, including mouse mammary and human breast epithelium, and it has been proposed that the SP phenotype is a universal stem cell marker. Studies of mouse and human breast SP suggest that the population is undifferentiated but capable of differentiating into epithelial structures of both luminal and myoepithelial lineages both in vitro and in vivo. However, evidence that the SP is enriched for stem cells is, at the moment, only correlative, and there are potentially confounding technical issues. We still await formal proof that the SP contains a stem cell population.
TL;DR: It is proposed that an I2 supplement should be considered as an adjuvant in breast cancer therapy because of its suppressive effect on the development and size of both benign and cancer neoplasias.
Abstract: This paper reviews evidence showing iodine as an antioxidant and antiproliferative agent contributing to the integrity of normal mammary gland. Seaweed is an important dietary component in Asian communities and a rich source of iodine in several chemical forms. The high consumption of this element (25 times more than in Occident) has been associated with the low incidence of benign and cancer breast disease in Japanese women. In animal and human studies, molecular iodine (I2) supplementation exerts a suppressive effect on the development and size of both benign and cancer neoplasias. This effect is accompanied by a significant reduction in cellular lipoperoxidation. Iodine, in addition to its incorporation into thyroid hormones, is bound into antiproliferative iodolipids in the thyroid called iodolactones, which may also play a role in the proliferative control of mammary gland. We propose that an I2 supplement should be considered as an adjuvant in breast cancer therapy.
TL;DR: In humans and cows, changes in milk calcium appear to be regulated by the amount of citrate and casein in milk rather than changes in [Ca2+], and nothing appears to be known about the mechanisms that mediate transport of calcium across the basolateral membrane of the alveolar cell.
Abstract: Ionized calcium ([Ca 2+ ]) is present in milk at concentrations around 3 mM, a concentration that drives the formation of complexes with citrate, phosphate, and casein, thereby generating compounds that carry the major portion of calcium in milk. In humans and cows, where it has been studied, changes in milk calcium appear to be regulated by the amount of citrate and casein in milk rather than changes in [Ca 2+ ]. Most or all of the calcium in milk is likely derived through exocytosis of secretory vesicles derived from the Golgi compartment where a calcium ATPase mediates transport from the cytoplasm. The identity of the transporters is not yet certain but gene expression for the plasma membrane calcium ATPase, PMCA2bw, and the secretory pathway calcium ATPase, SPCA, is highly upregulated during lactation. Currently nothing appears to be known about the mechanisms that mediate transport of calcium across the basolateral membrane of the alveolar cell.
TL;DR: The hypothesis that the function of vascular endothelial growth factor (VEGF) in breast cancer is not limited to angiogenesis, and that VEGF signaling in breast carcinoma cells is important for the ability of these cells to evade apoptosis, is advanced.
Abstract: This review advances the hypothesis that the function of vascular endothelial growth factor (VEGF) in breast cancer is not limited to angiogenesis, and that VEGF signaling in breast carcinoma cells is important for the ability of these cells to evade apoptosis and progress towards invasive and metastatic disease. In other terms, VEGF signaling provides a selective advantage for the survival and dissemination of breast carcinoma cells that may be independent of angiogenesis. The key component of this hypothesis is that breast carcinoma cells express specific VEGF receptors and that these receptors respond to autocrine VEGF, resulting in the activation of signaling pathways that impede apoptosis and promote cell migration. A related hypothesis, which is developed in this review, is that the α6β4 integrin, which has been implicated in the survival and motility of breast cancer cells, can stimulate the translation of VEGF mRNA and, consequently, autocrine VEGF signaling. These findings imply that VEGF and VEGF receptor-based therapeutics, in addition to targeting angiogenesis, may also target tumor cells directly.
TL;DR: An overview of the latest knowledge concerning the epidemiology, classification, clinical presentation, management, and physiopathology of benign breast diseases is presented.
Abstract: Benign breast diseases have always been neglected in comparison to cancer, despite the fact that there are many more patients with such diseases than patients presenting to a breast clinic for cancer. Like normal breast tissues, benign breast diseases are under a complex system of controls by both systemic hormonal and local factors. In this review, we attempt to present an overview of the latest knowledge concerning the epidemiology, classification, clinical presentation, management, and physiopathology of these disorders.
TL;DR: The regulation of OTR signaling in different cell systems is reviewed and how understanding the molecular basis of receptor coupling specificity has become extremely important for understanding the role played by OTRs in regulating cell growth is discussed.
Abstract: Oxytocin (OT) plays a crucial role as a mediator of breast myoepithelial cell contraction, the process responsible for the ejection of milk during lactation, and is also involved in myoepithelial cell proliferation and postpartum mammary gland proliferation. Furthermore, although a number of breast cancer cells have oxytocin receptors (OTRs), it has been reported that OT stimulates, inhibits, or has no effect on cell proliferation. As these different effects seem to be mediated by different signaling pathways elicited by OTR stimulation, we here review the regulation of OTR signaling in different cell systems and discuss how understanding the molecular basis of receptor coupling specificity has become extremely important for understanding the role played by OTRs in regulating cell growth.
TL;DR: The Rho family of GTPases is part of the Ras superfamily as mentioned in this paper and has been the subject of attention of researchers due to their vast spectrum of functions, including cell growth, motility, cell-cell adhesions, morphogenesis, cytoskeletal dynamics and cellular trafficking.
Abstract: The Rho family of GTPases is part of the Ras superfamily. The Rho, Rac, and Cdc42 members of the family are present in mammalian cells and have been the subject of attention of researchers due to their vast spectrum of functions. Rac 1, Cdc42, and RhoA are well-known for their role in the regulation of the actin cytoskeleton in promoting the formation of lamellipodia, filopodia, and stress fibers, respectively. The Rho proteins also participate in the control of cell growth, motility, cell-cell adhesions, morphogenesis, cytoskeletal dynamics, and cellular trafficking. The mechanisms for eliciting these functions have become clearer during the last decade. Concordant with their roles in multiple processes of cellular control, the Rho proteins have been shown to be involved in tumor growth, progression, metastasis, and now angiogenesis.
TL;DR: This work isolated and characterized cell populations enriched in normal mammary stem/progenitors and studied the expression of putative stem/ Progenitor markers in tumors derived from genetically engineered mice to address heterogeneity in breast cancers.
Abstract: Breast cancer is a genetically and clinically heterogeneous disease It is unclear whether different target cells contribute to this heterogeneity and which cell types are most susceptible to oncogenesis Stem cells are speculated to be the cellular origin of at least a subset of human breast cancers To begin to address these issues, we have isolated and characterized cell populations enriched in normal mammary stem/progenitors and have studied the expression of putative stem/progenitor markers in tumors derived from genetically engineered mice Specifically, transgenic activation of Wnt signaling in the mammary gland induces tumors comprised of epithelial and myoepithelial cells harboring the same genetic defect implying that the tumor arose from transformation of a bipotent progenitor cell On the other hand, transgenic activation of Neu signaling induces tumors comprising cells of more limited lineage capacity Thus, the heterogeneity of different breast cancers may reflect the activation of different oncogenic pathways, different cellular targets in which these genetic changes occur, or both
TL;DR: The evidence that two important entities, the extracellular calcium-sensing receptor (CaR) and parathyroid hormone-related protein (PTHrP) are involved in a feedback loop that regulates calcium fluxes to the mammary gland is summarized.
Abstract: Calcium is an important nutrient that is secreted into milk in quantities that put a considerable stress upon maternal calcium homeostasis. Here we summarize the evidence that two important entities, the extracellular calcium-sensing receptor (CaR) and parathyroid hormone-related protein (PTHrP) are involved in a feedback loop that regulates calcium fluxes to the mammary gland. The CaR may also play a role in regulating milk secretion, and may regulate the proliferation of normal and neoplastic mammary epithelial cells. Finally, the relationship between the CaR and PTHrP in breast cancer cells may promote the formation of osteolytic bone metastases.
TL;DR: It is demonstrated that pregnancy-induced mammary epithelial cells (PI-MECs) are cellular targets for pregnancy-enhanced mammary tumorigenesis and their important stem cell-like features, such as self renewal, as well as their ability to produce progeny with diverse cellular fates.
Abstract: The identification of cancer-initiating epithelial subtypes (i.e. cancer stem cells) is important for gaining a more comprehensive understanding of the process of neoplastic transformation and tumorigenesis. Since reproductive history has a major impact on breast tumorigenesis, it is reasonable to assume that pregnancy and lactation have enduring effects on the cancer susceptibility of multipotent progenitors. Using the Cre-lox technology as a tool to genetically label pregnancy-hormone-responsive cells, we identified a mammary epithelial subtype that is abundant in parous females. These pregnancy-induced mammary epithelial cells (PI-MECs) originate from differentiating cells during the first pregnancy and lactation cycle. They do not undergo apoptosis during postlactational remodeling, and they persist throughout the remainder of a female's life. In this review, we discuss the biological relevance of PI-MECs in multiparous females and their important stem cell-like features, such as self renewal, as well as their ability to produce progeny with diverse cellular fates. Using appropriate animal models, we further demonstrate that PI-MECs are cellular targets for pregnancy-enhanced mammary tumorigenesis.
TL;DR: This review addresses recent findings concerning the histology and molecular physiology of putative bovine mammary stem and progenitor cell populations, areas where more study is critically needed, and areas where studies of bovines mammary physiology may present a unique opportunity to better understand mammARY physiology in many species.
Abstract: Although cell number is positively correlated with milk production, much remains to be learned about the bovine mammary stem cell and progenitor cells. Bovine mammary development is driven by many of the same classic mammogenic hormones studied in murine models, yet histologic features of bovine mammary development differ from that of rodent models. Most notably, terminal end buds, as they have been described for murine models, do not exist in the bovine mammary gland. However, among the most important common features of mammary development in disparate species is the involvement of histologically distinct, lightly staining epithelial cells as putative stem and progenitor cells. Although stem cell research has often focused on mammary development, mammary stem cells seemingly provide the basis for mammary growth and cell turnover in the mature animal. These cells provide an obvious focus for research aimed at increasing the efficiency of milk production. This review addresses recent findings concerning the histology and molecular physiology of putative bovine mammary stem and progenitor cell populations, areas where more study is critically needed, and areas where studies of bovine mammary physiology may present a unique opportunity to better understand mammary physiology in many species.
TL;DR: The available evidence suggests that breast cancer risk can be reduced by early dietary intervention, and lifetime protection may be achieved if one is exposed to a dietary factor that lowers Breast cancer risk early in life.
Abstract: Multiple factors contribute to the development of human breast cancer. However, environmental factors, especially dietary factors, appear to have the greatest effects. Evidence obtained in epidemiological studies has been corroborated by laboratory findings. Dietary components strongly associated with breast cancer include fat and phytochemicals. A diet high in n-3 polyunsaturated fatty acid (PUFA) or monounsaturated fatty acid (MUFA) and low in n-6 PUFA is protective against breast cancer. Some phytochemicals present in fruits and vegetables are also protective. Time of intake appears to be important: lifetime protection may be achieved if one is exposed to a dietary factor that lowers breast cancer risk early in life. Synergistic and antisynergistic interactions between dietary factors can modify breast cancer risk. The available evidence suggests that breast cancer risk can be reduced by early dietary intervention.
TL;DR: Mouse mutants with changes in the gene expression pattern characteristic of the basal myoepithelial cell layer have been generated and used to show that these cells influence the proliferation, survival and differentiation of luminal cells, modulate stromal–epIthelial interactions and actively participate in mammary morphogenesis.
Abstract: Until recently, myoepithelial cells—the second major cell population in the mammary epithelium—were not considered to play an important role in the morphogenetic events during gland development. Mouse mutants with changes in the gene expression pattern characteristic of the basal myoepithelial cell layer have been generated and used to show that these cells influence the proliferation, survival and differentiation of luminal cells, modulate stromal–epithelial interactions and actively participate in mammary morphogenesis. Various cellular and molecular mechanisms may underlie the observed phenotypes. These include an unbalanced expression of matrix degrading metalloproteinases (MMPs) and their inhibitors, leading to changes in the composition and organization of the (extracellular matrix) ECM, the production of soluble growth factors affecting stromal and epithelial cell growth and differentiation and direct signaling through cell–cell contacts between the myoepithelial and luminal cell layers.
TL;DR: An overview of the literature on intrauterine breast development with special emphasis on the myoepithelial component of the fetal human mammary gland epithelium and the relevance of developmental, morphological fetal tissue-based studies to the understanding and the clinical management of adult diseases is provided.
Abstract: As their name implies, the myoepithelial cells found at the epithelial-mesenchymal interface of the human mammary gland disclose features suggestive of a dual epithelial-like and muscle-like differentiation, i.e. they co-express various keratins and vimentin intermediate filaments, as well as smooth muscle-related antigens. This article provides an overview of the literature on intrauterine breast development with special emphasis on the myoepithelial component of the fetal human mammary gland epithelium. It discusses original and recently published immunohistochemical data on myoepithelial precursors and reasserts the relevance of developmental, morphological fetal tissue-based studies to the understanding and the clinical management of adult diseases.
TL;DR: Several anti-VEGF agents are now being tested in patients with breast cancer, and adjuvant therapy trials are in development, and important questions remain regarding the biology and clinical development of these agents in breast cancer.
Abstract: Vascular Endothelial Growth Factor (VEGF) plays an important role in multiple physiologic and pathologic processes involving endothelial cells. Several preclinical and clinical sources of evidence suggest its importance in human breast cancer. Based on the presumed biologic relevance of VEGF in human breast cancer, clinical trials using agents targeting VEGF were launched beginning in the late 1990s. This clinical trial effort came to fruition in 2005 with the success of the first large, prospective randomized trial of anti-VEGF therapy in patients with front-line metastatic breast cancer, which demonstrated the benefit of adding the monoclonal anti-ligand antibody bevacizumab to the chemotherapeutic agent paclitaxel. Based upon this success, numerous anti-VEGF agents are now being tested in patients with breast cancer, and adjuvant therapy trials are in development. Nevertheless, important questions remain regarding the biology and clinical development of these agents in breast cancer.
TL;DR: One type of tumor with myoepithelial features, the so-called ‘basal’ breast cancer, has received a renewed interest, although it has been known to pathologists for more than two decades and is now being studied using antibodies against some new molecules that have emerged from studies of sorted normal luminal and myoEPithelial cells.
Abstract: Until recently the myoepithelial cell has been studied relatively little in terms of its role in breast cancer. A number of malignancies showing myoepithelial differentiation have been reported in the literature, although they are still thought to be relatively rare and only limited studies are published. As a result of recent expression profiling experiments, one type of tumor with myoepithelial features, the so-called 'basal' breast cancer, has received a renewed interest, although it has been known to pathologists for more than two decades. These tumors, which express markers of both luminal and myoepithelial cells, are now being studied using antibodies against some new molecules that have emerged from studies of sorted normal luminal and myoepithelial cells. These immunohistochemical data, combined with genomic studies, may lead to better identification and management of patients with 'basal' tumors.
TL;DR: The present review discusses the current approaches to address breast tissue homeostasis, cell-type diversification in general and breast cancer evolution in particular and the measures taken to unravel and maintain cell type diversification for further investigation.
Abstract: Recent genome-wide expression analysis of breast cancer has brought new life to the classical idea of tumors as caricatures of the process of tissue renewal as envisioned by Pierce and Speers (Cancer Res 1988;48:1996-2004) more than a decade ago. The search for a cancer founder cell or different cancer founder cells is only possible if a hierarchy of differentiation has been established for the particular tissue in question. In the human breast, the luminal epithelial and myoepithelial lineages have been characterized extensively in situ by increasingly elaborate panel of markers, and methods to isolate, culture, and clone different subpopulations have improved dramatically. Comparisons have been made with the mouse mammary gland in physiological three-dimensional culture assays of morphogenesis, and the plasticity of breast epithelial cells has been challenged by immortalization and transformation. As a result of these efforts, several candidate progenitor cells have been proposed independently of each other, and some of their features have been compared. This research has all been done to better understand breast tissue homeostasis, cell-type diversification in general and breast cancer evolution in particular. The present review discusses the current approaches to address these issues and the measures taken to unravel and maintain cell type diversification for further investigation.
TL;DR: The pathophysiology of hypercalcemia in breast cancer patients mimics the physiological processes that normally regulate calcium metabolism during lactation, which relies on the inhibition of bone resorption by a class of drugs known as bisphophonates.
Abstract: Hypercalcemia is a frequent complication of breast cancer which causes significant morbidity and mortality. Most commonly, it occurs in patients with multiple skeletal metastases. However, in a significant minority of patients, calcium levels become elevated in the absence of skeletal disease. In both instances, hypercalcemia is the result of pathological bone resorption caused by the secretion of cytokines that stimulate osteoclast differentiation and activity. One of these cytokines is parathyroid hormone-related protein (PTHrP). PTHrP is also secreted by normal breast cells during lactation to increase bone resorption and liberate skeletal calcium stores for the purposes of milk production. Therefore, the pathophysiology of hypercalcemia in breast cancer patients mimics the physiological processes that normally regulate calcium metabolism during lactation. Current therapy for hypercalcemia in breast cancer patients relies on the inhibition of bone resorption by a class of drugs known as bisphophonates. Newer therapies in development target cytokines involved in the recruitment and activation of osteoclasts by tumor cells.
TL;DR: Strategies to harness hypoxia as a trigger for oncolytic viral gene expression in breast cancer, thereby increasing the specificity of viral infection, replication, and cytotoxicity to hypoxic areas of tumor are described.
Abstract: Hypoxia is a common tumor condition associated with metastases, therapeutic resistance, and poor patient survival. Forty percent of breast cancers are hypoxic, with a median oxygen concentration of 3.9%, and a third of tumors have regions less than 0.3%. Normal breast tissue is reported to have oxygen concentrations greater than 9%. This tumor hypoxia in breast cancer confers resistance to conventional radiation therapy and chemotherapy, as well as making estrogen-receptor-positive tumors less sensitive to hormonal therapy. Novel treatment modalities are needed to target hypoxic tumor cells. Lower tumor oxygen levels compared with surrounding normal tissues may be utilized to target and enhance herpes oncolytic viral therapy in breast cancer. Attenuated oncolytic herpes simplex viruses offer a unique cancer treatment by specifically infecting, replicating within, and lysing tumor cells. They carry genetically engineered mutations to reduce their virulence and attenuate their ability to infect normal tissues. Studies have shown the safety and efficacy of oncolytic herpes simplex viruses in treating breast cancer both in humans and in preclinical models. The placement of essential viral genes under the control of a hypoxia-responsive enhancer, which is upregulated selectively in hypoxic tissue, represents a promising strategy to target oncolytic viruses precisely to hypoxic cancer cells. In this review we describe strategies to harness hypoxia as a trigger for oncolytic viral gene expression in breast cancer, thereby increasing the specificity of viral infection, replication, and cytotoxicity to hypoxic areas of tumor. Such a targeted approach will increase efficacy in the therapy of hypoxic tumors while achieving a reduction in total dose of viral therapy.
TL;DR: Until the breast is seen as the integrated organ that it is, the authors will not be able to understand either breast cancer or normal breast function, the invited chapters in this issue show.
Abstract: The importance of the microenvironment and context in regulation of tissueand organ-specific functions, as well as in progression to malignancy, is beginning to be recognized by the larger scientific community. It is true that no cell is an island, and this fact has been clearly demonstrated for the mammary gland, an organ that has provided much of the pioneering work in this area and lends itself to detailed analysis of the molecular mechanisms involved. This issue of Journal of Mammary Gland Biology and Neoplasia was conceived to bring more balance to the research on the breast and breast diseases. For decades, there has been an overwhelming emphasis on the luminal epithelial/secretory cells of the mammary gland, but the myoepithelial cell has largely been ignored. Even when believed to be important, its significance has been explored only in lactation, where it facilitates milk secretion via oxytocin-induced contraction. Only recently has a serious study of the myoepithelial cell as a legitimate contributor to normal function and breast cancer begun. The invited chapters in this issue show that until we begin to see the breast as the integrated organ that it is, we will not be able to understand either breast cancer or normal breast function. This integration is not just among the different cell types of the