Showing papers in "Journal of Mammary Gland Biology and Neoplasia in 1999"
TL;DR: The experience with the histopathology of human and mouse mammary disease is viewed by comparing the normal gland with hyperplastic, dysplastic and neoplasticlesions of traditional and transgenic origin.
Abstract: The mouse has emerged as a primary animal model for human breast cancer because the mammary glands of the two species are very similar in structure and function. In this regard the TDLU and LA have similar morphology. The mouse, infected by MMTV, develops "spontaneous" tumors with specific but limited tumor phenotypes. The advent of genetic manipulation has created transgenic mice that develop hyperplasias and tumors morphologically and cytochemically comparable to lesions in humans. Even experienced pathologists have difficulty distinguishing between lesions from the two species, and the morphological similarities support the utility of the mouse model in understanding human breast cancer. In this essay we review our experience with the histopathology of human and mouse mammary disease by comparing the normal gland with hyperplastic, dysplastic and neoplastic lesions of traditional and transgenic origin.
256 citations
TL;DR: Differences between the morphological development of the mammary parenchyma in rodents, humans, and ruminant dairy animals are highlighted, placing emphasis on differences in the cellular composition and structure of the Mammary fat pad.
Abstract: The growth and morphogenesis of mammary parenchyma varies substantially between species and is regulated by an array of systemic and local factors. Central to this regulation is the mammary fat pad, a matrix of adipose and connective tissue capable of mediating hormone action and synthesizing an array of growth regulatory molecules. In this article we highlight differences between the morphological development of the mammary parenchyma in rodents, humans, and ruminant dairy animals, placing emphasis on differences in the cellular composition and structure of the mammary fat pad. While a great deal remains to be understood about the ability of stroma to locally regulate mammary development, the significance of its contribution is becoming increasingly apparent. The actions of several steroid and peptide hormones appear to be mediated by an array of growth factors, proteases and extracellular matrix components synthesized by constituents of the mammary fat pad. Further, mammary adipose tissue represents a significant store of lipid which, by itself and through its derivatives, could influence the growth of mammary epithelium in diverse ways. This review describes the integral role of the mammary fat pad during mammogenesis, emphasizing the point that species differences must be addressed if local growth and morphogenic mechanisms within the mammary gland are to be resolved.
221 citations
TL;DR: Increased apoptosis and cell proliferation, relative to that in lactating glands during the same stage of gestation, suggest that a nonlactating period serves to promote cellturnover prior to the next lactation.
Abstract: Lifetime milk production is maximized when dairy cows are pregnant during approximately 70% of each lactation. Between lactations, a nonlactating period is necessary for optimal milk production in the succeeding lactation. With cessation of milking, alveolar structure is largely maintained and little or no loss of cells occurs. However, increased apoptosis and cell proliferation, relative to that in lactating glands during the same stage of gestation, suggest that a nonlactating period serves to promote cell turnover prior to the next lactation. Even in the absence of pregnancy, mammary involution in dairy animals occurs at a slower rate than in rodents; alveolar structure is maintained for several weeks and lactation can be reinitiated after four weeks or more of involution. Although apoptosis appears to be initiated within a similar time frame to that in rodents, the maximum proportion of apoptotic epithelial cells appears to be lower than in rodents, and apoptosis may be accompanied by an initial increase in cell proliferation. The ability to manipulate apoptosis and cell proliferation during the nonlactating period and during lactation is expected to provide enormous benefits to the dairy industry.
206 citations
TL;DR: Evidence that mammary epithelialcells from late embryonic stages are already capable of synthesizing milk proteins when subjected to appropriatehormonal stimulation is provided.
Abstract: Development of the mammary glands is initiated in the embryo but the major part of their development occurs in the adult. While development in puberty and pregnancy is dependent on hormones, prenatal and early postnatal development appear to progress autonomously. Mutual and reciprocal epithelial-mesenchymal interactions are critical for both phases of development. Specific steps such as the formation of the bud, the first appearance of hormone receptors, formation of the primary sprout and ductal elongation have been shown to be governed by epithelial-mesenchymal signaling. In recent years, some of the signaling molecules that are required in these processes have been identified through gene inactivation. We discuss the potential role of these factors in mediating growth and differentiation. In addition we provide evidence that mammary epithelial cells from late embryonic stages are already capable of synthesizing milk proteins when subjected to appropriate hormonal stimulation.
190 citations
TL;DR: Local control of apoptosis in rodents during weaning, and after peak lactation in dairyanimals, may be due to the actions of milk-bornesurvival factors or their inhibitors, and can bemanipulated by frequency of milk removal.
Abstract: Lactation depends on regular suckling or milkingof the mammary gland. Without this stimulus, milksecretion stops and mammary involution is induced.Involution caused by abrupt cessation of milk removal is characterized by de-differentiation andapoptosis of mammary epithelial cells, the extent andtime course of the latter varying between species.Apoptosis is inhibited and milk secretion is restored by re-suckling, if milk stasis is of shortduration. Mammary involution and apoptosis also occurduring weaning, even in concurrently-pregnant animalswhen the interval between lactations is restricted, suggesting that tissue remodeling is essentialfor subsequent lactation. Declining milk production inruminants after peak lactation is also associated with,and probably results from, net cell loss by apoptosis. Involution and apoptosis arecontrolled by changes in systemic galactopoietic hormonelevels, and by intra-mammary mechanisms responsive tomilk removal. Milk stasis precipitated by litter removal or cessation of milking may involveintra-mammary control related to physical distension ofthe epithelium. Local control of apoptosis in rodentsduring weaning, and after peak lactation in dairyanimals, may be due to the actions of milk-bornesurvival factors or their inhibitors, and can bemanipulated by frequency of milk removal.
163 citations
TL;DR: The PUFA composition of human milk, factors which determine and modulate milk PUFA content, and possible effects of milk LC-PUFA on infant growth and development are discussed.
Abstract: The lipid fraction of human milk represents the main source of energy for the newborn infant and supplies essential nutrients such as fat-soluble vitamins and polyunsaturated fatty acids (PUFA). The essential fatty acids linoleic and alpha-linolenic acids are precursors of long-chain polyunsaturated fatty acids (LC-PUFA), such as arachidonic (C20:4 n-6) and docosahexaenoic (C22:6 n-3) acids, present in human milk in considerable amounts. LC-PUFA are indispensable structural components of all cellular membranes, and they are incorporated in relatively large amounts during early growth of the brain and the retina. Moreover, some LC-PUFA are precursors of eicosanoids, molecules with potent biological activity that modulates various cellular and tissue processes. The supply of long-chain fatty acids has been associated with functional outcomes of the recipient infants such as visual acuity and development of cognitive functions during the first year of life. Here we discuss the PUFA composition of human milk, factors which determine and modulate milk PUFA content, and possible effects of milk LC-PUFA on infant growth and development.
152 citations
TL;DR: The Bcl-2 gene family regulates tissuedevelopment and tissue homeostasis through the interplay of survival and death factors and is salient to both normal mammary gland physiology and the development of new therapeutic approaches to breast cancer.
Abstract: The Bcl-2 gene family regulates tissuedevelopment and tissue homeostasis through the interplayof survival and death factors. Family members arecharacterized as either pro-apoptotic or anti-apoptotic, depending on cellular context. In addition toits anti-apoptotic effect, Bcl-2 also inhibitsprogression through the cell cycle. Functionalinteractions between family members as well as bindingto other cellular proteins modulate their activities.Mammary gland tissue, similar to many other tissues,expresses a number of different Bcl-2 relativesincluding bclx, bax, bak, bad, bcl-w, bfl-1, bcl-2 aswell as the bcl-2 binding protein Bag-1. Bcl-2 isexpressed in the nonpregnant mammary gland and earlypregnancy. In contrast, expression of bcl-x and baxcontinues through late pregnancy, is down-regulated during lactation, and upregulated with thestart of involution. Bak, bad, bcl-w, and bfl-1 are alsoup-regulated during involution. The specific roles ofindividual gene products are investigated using dominant gain of function and loss of functionmice. Finally, different Bcl-2 family members arecommonly over- or under-expressed in human breastcancers. Bcl-2 expression in human breast cancers hasbeen associated with a good prognosis, whiledecreased Bax expression has been linked to poorclinical outcome. Understanding the role Bcl-2 familymembers play in regulating mammary epithelial cellsurvival is salient to both normal mammary glandphysiology and the development of new therapeuticapproaches to breast cancer.
128 citations
TL;DR: Disruption of the genes for PRLand the PRL receptor, as well as those for transcription factors important in mammary gland regulation(Stat proteins), have provided a new set of animal models with which to study normal mammary glands development and the relationships of PRL to breastcarcinogenesis.
Abstract: Prolactin (PRL) regulates the development of the mammary gland at three stages in the reproductive life history of females. The first stage is mammary gland organogenesis, during which PRL contributes to the maturation of the mammary glands from a primary ductal system, which grows from terminal end buds, to the fully mature nonpregnant gland. The mature mammary gland is characterized by an absence of terminal end buds, and the development of a highly branched architecture, which is decorated by lobular buds. During pregnancy PRL, placental lactogens, and progesterone stimulate the expansion and physiological differentiation of the lobuloalveolar system from the lobular buds. After delivery PRL, in the context of falling progesterone, stimulates the final induction of milk protein gene expression and lactation. PRL acts directly on the mammary epithelium, and indirectly by stimulating luteal progesterone secretion in rodents. Disruption of the genes for PRL and the PRL receptor, as well as those for transcription factors important in mammary gland regulation (Stat proteins), have provided a new set of animal models with which to study normal mammary gland development and the relationships of PRL to breast carcinogenesis. Two major deficiencies in our current knowledge of PRL actions are our understanding of the role of epithelial-stromal interactions in PRL-induced mammary morphogenesis, and the identity of developmentally important genes that are regulated by PRL during normal mammary gland organogenesis.
121 citations
TL;DR: A complexdynamic pattern of cell death-inducing and survivalfactors that promote the development of the maturemammary gland and that rapidly remodel the tissue afterlactation is described.
Abstract: Programmed cell death (apoptosis) occursregularly during normal growth and development of themammary gland. One of the most dramatic examples ofapoptosis is evident during the remodeling of the breast that accompanies postlactational involution.Transgenic mouse models have demonstrated thatoverexpression of polypeptides such as transforminggrowth factor alpha (TGFα)3 and insulinlike growth factor I (IGF-I) can block this remodeling, suggestingthat these growth factors may be acting as survivalfactors for the mammary epithelium. In contrast,transgenic mice that overexpress the growth inhibitor transforming growth factor beta (TGF-β)show increased apoptosis in the mammary epitheliumthroughout mammary development, suggestive of amechanism working to counterbalance the survivalfactors. Experiments with mammary epithelial cell lines cultured invitro have confirmed that these growth factors canindeed regulate apoptosis and survival in mammaryepithelial cells; EGF, IGF-I, and basic fibroblastgrowth factor (bFGF) act as survival factors formammary epithelial cells, while TGF-β induces theirdeath. In breast cancer, cytotoxic drugs and hormoneablation increase the expression of TGF-β, which may function to induce cell death by eitherparacrine or autocrine mechanisms. Lastly, although ithas very limited expression in the breast, TNFαhas been shown to be effective in the rapid, direct induction of cell death in breast cancer celllines. Together, these studies describe a complexdynamic pattern of cell death-inducing and survivalfactors that promote the development of the maturemammary gland and that rapidly remodel the tissue afterlactation.
104 citations
TL;DR: In this review, molecular mechanisms by which cell-matrix interactions contribute to cell survival are considered, and their role inammary gland development and function is discussed.
Abstract: Tissue architecture in multicellular organismsis maintained through adhesive interactions betweencells and their neighbors, and between cells and theunderlying extracellular matrix. These interactions are important in the dynamic regulation oftissue organization as well as the control of cellproliferation, differentiation and apoptosis. Theultimate goal of this regulation is to promote cellgrowth and differentiation only when the cell is inthe correct location, and to delete cells that havebecome displaced from their proper environment. Ittherefore plays an important role in development andtissue remodeling. In this review we consider themolecular mechanisms by which cell-matrix interactionscontribute to cell survival, and discuss their role inmammary gland development and function.
101 citations
TL;DR: Questions with broad biological implications for the Hennighausen and colleagues, in a recent review development of many organs and tissues in a variety, cite evidence that more than 8,300 publications on of organisms are cited.
Abstract: questions with broad biological implications for the Hennighausen and colleagues, in a recent review development of many organs and tissues in a variety (1) cite evidence that more than 8,300 publications on of organisms. Much of the emergence of the mammary the development and secretions of the mammary gland gland as a model system is due to powerful experimenhad been published by 1899. The term a development,o tal techniques that are uniquely available to pracwhen used in reference to mammary biology, is broadly titioners of mouse mammary research. It is not an interpreted, since the mammary apparatus is repeatedly exaggeration to say that scientists not previously familgrowing, reshaping, destroying and renewing itself in iar with mammary research are astonished when first synchrony with reproductive statusÐ a developingo learning the power of these techniques. The interseceven in the adult. Even so 8,300 is an impressive tion of modern methods of modifying and analyzing number, particularly when considering that it is only the mouse genome with pre-existing mammary techa prelude to the avalanche of literature in the present nologies for transplantation and other manipulations, century. Historically, mammary gland research has makes the mammary gland the system of choice for been driven by a few dominant interests. One is the many studies in developmental genetics. In what other issue of infant nutrition and the need to understand system can the epithelium be rescued from moribund this marvelous milk-producing device that defines our mutants (even embryos) and transplanted, regenerating class Mammalia, a matter involving both public health a new gland in which the phenotype can be readily and agricultural interests. A second is the cancer probidentified, analyzed, and even used to create serially lem, certainly one of the most pressing health issues propagated tissue lines? These transplantation techof our time and one that particularly engages the emoniques make possible tissue recombinantsÐ genetic tions, striking, as it often does, women in the prime chimerasÐ in which the relative contributions of epiof life. And there is of course our less goal-oriented thelium and stroma can be evaluated. Mammary cells a academico interest in the basic biology of the breast, can be grown and genetically manipulated in culture, an interest which underlies and supports other research, then implanted into gland-free fat pads to regenerate and which ultimately will provide a coherent intellecnew variants. These manipulations can be carried out tual framework upon which we can base long-term on glands in adult animals, easily exposed and large progress in the understanding of both infant nutrition enough to be readily manipulated. These and other and breast disease. experimental techniques were reviewed by Medina in In the past thirty years or so another thread has the first issue of this Journal (2) and a forthcoming become increasingly prominent, one that is abundantly special issue will be devoted to a comprehensive
TL;DR: Research is needed to understand factors affecting the transfer of vitamin A to milk, and to evaluate various strategies for improving the vitamin A status of mothers and infants.
Abstract: Because of the many functions of vitamin A inhuman physiology, deficiency or excess of the vitamin inlactating women or their infants can adversely affecttheir health. Infants are born with low body stores of vitamin A, and rely on vitamin A inmilk to meet their needs. The vitamin A content of milkis related to maternal vitamin A status and maternaldietary vitamin A intake during lactation. Low-income lactating women in non-industrialized countrieshave lower milk vitamin A concentrations than lactatingwomen in industrialized countries. Supplementation oflactating women in non-industrialized countries with vitamin A or beta-carotene has resulted inincreased milk vitamin A concentrations. However, theoptimal timing and dose for sustaining adequate levelsof vitamin A in milk throughout the lactation period has not been determined. Furtherresearch is needed to understand factors affecting thetransfer of vitamin A to milk, and to evaluate variousstrategies for improving the vitamin A status of mothers and infants.
TL;DR: It is shown that both a basement membrane and an organized tissue structure are required to achieve sustained mammary cellsurvival and these models could now be used to investigate how the basement membrane represses apoptosis in normalcells, and how breast cancers becomedath-resistant.
Abstract: Mammary tissue homeostasis depends upon dynamic interactions between the epithelial cells, their microenvironment (including the basement membrane and the stroma), and the tissue architecture, which influence each other reciprocally to regulate growth, death and differentiation in the gland. To study how apoptosis is regulated in normal mammary cells, and to understand its role in breast tumor pathogenesis, we need model systems that recapitulate breast tissue architecture and microenvironment in culture. We have established culture models of primary and established nonmalignant mammary cell lines from both rodent and human, and defined procedures to study how cell and tissue architecture affect signaling by the basement membrane. We show that both a basement membrane and an organized tissue structure are required to achieve sustained mammary cell survival. These models could now be used to investigate how the basement membrane represses apoptosis in normal cells, and how breast cancers become death-resistant.
TL;DR: Developing evidence for the presence ofstem cells in virtually every renewing mammalian tissue as well as some classically considered to consist only of differentiated cells is presented.
Abstract: It has recently been shown that the progeny froma single cell may comprise the epithelial population ofa fully developed lactating mammary outgrowth in mice.Serial transplantation of epithelial fragments from this clonally derived gland demonstratesthat the subsequently generated outgrowths are alsocomprised of progeny from the original antecedent.Similarly, genetic analysis of contiguous portions of individual human mammary ducts within the samebreast indicates their clonal derivation. Theseobservations support the concept that multipotenttissue-specific epithelial stem cells are present amongthe parenchymal cells of the mammary gland. Here,we present the developing evidence for the presence ofstem cells in virtually every renewing mammalian tissueas well as some classically considered to consist only of differentiated cells. Further, wereview the present morphologic and biologic evidence forstem cells and lineage-limited progenitor cells in humanand rodent mammary epithelium. Although a number of selective markers are known for variouslineage-limited hematopoietic cells and their progeny,our understanding of the biology of the precursor cellsfor mammary epithelium is just beginning. Our purpose here is to develop further interest in theclarification of these issues in the biology of themammary gland.
TL;DR: Resoration of ovarian hormone production anddecreased production of PTHrP2 are likely to result in the recovery of bone mineral after lactation has ceased, according to current data.
Abstract: Lactating women secrete approximately 250 mg of calcium in breast milk each day. Some of the calcium used for milk production comes from bone as women experience a transient 3-9% decrease in bone density during lactation. This loss appears to be obligatory and under hormonal regulation as lactation-induced bone loss occurs even when calcium intake is high. Bone mineral is recovered after lactation ceases or menses resume. Recovery of bone mineral appears to be complete even when pregnancies and lactations are closely spaced, and lactation does not increase future risk of osteoporotic fracture. Current data point to estrogen and parathyroid hormone-related peptide as regulating bone mobilization during lactation. The typical calcium regulatory hormones, parathyroid hormone, calcitriol and calcitonin, do not appear to stimulate bone resorption during lactation. Restoration of ovarian hormone production and decreased production of PTHrP2 are likely to result in the recovery of bone mineral after lactation has ceased.
TL;DR: It is likely that clearance of apoptotic cells is critical to normal remodeling of the gland in preparation for the next wave of lactation, and the mammary gland provides an ideal organ in which to study the mechanisms and consequences of apoptosis invivo.
Abstract: Engulfment by a phagocyte is the final commonevent in the life of most apoptotic cells. Phagocytosisof apoptotic bodies prior to their lysis prevents therelease of potentially toxic or immunogenicintracellular contents and activates an anti-inflammatoryresponse, at least in macrophages. We are beginning tounderstand the mechanisms by which macrophages and otherphagocytes recognize apoptotic cells in vitro, but we are a long way from determining theirrelative importance in vivo. The involuting mammarygland undergoes massive cell loss by apoptosis. Thedying alveolar epithelial cells can be shed into the lumen or can be phagocytosed by macrophages andviable epithelial cells. Yet we know virtually nothingabout the mechanisms mediating recognition and uptake inthe mammary gland. It is likely that clearance of apoptotic cells is critical to normalremodeling of the gland in preparation for the next waveof lactation. The mammary gland, therefore, provides anideal organ in which to study the mechanisms and consequences of apoptotic cell clearance invivo.
TL;DR: These studies reveal that the consequences ofprogesterone signaling through progesterone receptor maydepend on the cell context, cell-cell and cell-extracellular matrix interactions, the dynamics ofPR turnover and the fate of PR positivecells.
Abstract: Progesterone was identified as a mammogenichormone several years ago but until now its precise rolein mammary development has remained obscure. Recentlywith the generation of several transgenic mouse models and development of reagents for analysisof progesterone receptor expression, the role ofprogesterone signaling in mammary development isbecoming more clear. The most significant observationsto emerge from these studies are (1) progesteronereceptors (PR)4 are present in a heterogeneous manner inthe epithelial cells and undetectable in the surroundingfat pad; (2) they are essential for lobuloalveolar and not for ductal morphogenesis; (3)progesterone signaling through progesterone receptors,leading to lobuloalveolar development, is initiated inthe epithelium and may occur through paracrinemechanisms; and (4) a regulated expression of the twoisoforms of progesterone receptor is critical formaintaining appropriate responsiveness to progesteroneand hence, epithelial cell replicative homeostasis.These studies also reveal that the consequences ofprogesterone signaling through progesterone receptor maydepend on the cell context, cell-cell andcell-extracellular matrix interactions, the dynamics ofPR turnover and the fate of PR positivecells.
TL;DR: The current knowledge of the mechanisms underlying PTHrP actions during normal mammary development and in breast cancer are discussed.
Abstract: Parathyroid hormone-related protein (PTHrP) wasoriginally identified as the tumor factor responsiblefor a clinical syndrome known as humoral hypercalcemiaof malignancy. It is now appreciated that PTHrP3 is a developmental regulatory moleculeexpressed during the formation of a wide variety oforgans. Recently, our laboratory has demonstrated thatPTHrP is necessary for mammary gland development. Ourstudies have suggested that this molecule participatesin the regulation of epithelial-mesenchymal interactionsduring embryonic mammary development and perhaps alsoduring adolescent ductal morphogenesis. In addition, it has been suggested that PTHrP plays acritical role in the establishment of bone metastases inbreast cancer. In this article, we will discuss thecurrent knowledge of the mechanisms underlying PTHrPs actions during normal mammary development andin breast cancer.
TL;DR: Signaltransduction events such as activation of protein kinaseA and JNK3 and changes in the activity ofseveral transcription factors including Stat5, Stat3, NF1, Oct-1, and AP-1 during the early and late phases of mammary glandinvolution are described.
Abstract: Maintenance of mammary epithelial differentiation and milk production during lactation is a consequence of milk removal and the presence of lactogenic hormones, particularly glucocorticoids, insulin and prolactin. After weaning the fall in lactogenic hormones and milk stasis lead to involution, a process that is mainly characterized by three events: (i) downregulation of milk protein gene expression, (ii) loss of epithelial cells by apoptosis and, (iii) tissue remodeling and preparation of the gland for a new pregnancy. Each of these processes is likely to depend on the activity of specific sets of transcription factors in the mammary epithelium and stroma that ensure the timely and spatially coordinated expression of critical gene products such as mediators of apoptosis (e.g., caspase-1 and regulators of tissue remodeling events (e.g., matrix metalloproteinases). Here we describe signal transduction events such as activation of protein kinase A and JNK and changes in the activity of several transcription factors including Stat5, Stat3, NF1, Oct-1, and AP-1 during the early and late phases of mammary gland involution. We discuss their possible role in regulating and coordinating involution with emphasis on the apoptotic process of involution.
TL;DR: The focus of this review is to discuss integrin-dependent functions that can be manipulated astargets for the therapeutic intervention of breastcancer.
Abstract: The differentiation and function of mammary epithelial cells is dependent upon the combined action of growth factor/hormone receptors and integrin receptors, which act in concert to control the signals required for normal cell function. It is now becoming clear that integrin receptors also contribute to carcinoma cell behavior and that alterations in expression and function during transformation have a large impact on breast carcinoma progression. The focus of this review is to discuss integrin-dependent functions that can be manipulated as targets for the therapeutic intervention of breast cancer. A combination of correlative and mechanistic studies have contributed to the identification of specific integrin receptors, namely alpha2beta1, alpha6beta1, and alpha6beta4, implicated in breast carcinoma progression. Although this field is still emerging and much remains to be learned, potential integrin-dependent signaling targets have been identified.
TL;DR: Evidence gleaned from descriptive data suggests that theapoptosis-related genes of the Bcl-2 gene family, tissue remodeling genes, protein tyrosine kinases andmaster genes ofThe homeotic gene cluster may be involved in determining epithelial cell fate during the estrous cycle.
Abstract: In the absence of pregnancy, the adult mammarygland is subjected to cyclic fluctuations of hormonalstimulation that constitute the estrous and menstrualcycles The mammary epithelium responds to these systemic hormonal changes by regionalproliferation, differentiation and cell death byapoptosis The fact that the mammary epithelial responseinvolves only a minor subset of the epithelial cellsimplies a delicate local control of epithelial cellfate resulting in either cell death or survivalEvidence gleaned from descriptive data suggests that theapoptosis-related genes of the Bcl-2 gene family, tissue remodeling genes, protein tyrosine kinases andmaster genes of the homeotic gene cluster may beinvolved in determining epithelial cell fate during theestrous cycle
TL;DR: Understanding of mammary gland involution is far interest to cell and developmental biologists, and apoptosis and tissue remodeling is of fundamental understanding of mammaries involution.
Abstract: involution and the factors that control apoptosis of nism by which women are protected from breast canmammary epithelial cells during normal development cer, and apoptosis during breast tumorigenesis and tumorigenesis. An understanding of involution and modulates tumor growth. Many chemotherapeutic apoptosis is essential to scientists from the several agents reduce tumor burden by the induction of different branches of mammary gland biology. For apoptosis in tumor cells. The multiple circumstances agricultural scientists methods to increase survival of under which mammary apoptosis occurs raise a fundamammary epithelial cells in late lactation may improve mental question: is mammary epithelial cell apoptosis the efficiency of milk production in dairy animals. controlled by the same molecular and genetic factors Specific induction of mammary epithelial cell death no matter when it occurs, or, are specific pathways is of vital importance to breast cancer researchers. The induced under different physiological and pathophysimolecular interplay between intracellular and extracelological circumstances? lular factors that regulate mammary involution, Although it has been extensively studied, our apoptosis and tissue remodeling is of fundamental understanding of mammary gland involution is far interest to cell and developmental biologists. Molecufrom complete. Lactation is an enduring feature of lar biologists focus on genes that control apoptosis mammalian reproduction. Virtually all human societies and their regulation. Finally, physiologists attempt to
TL;DR: Evidence is presented which suggests that the NF-κBfamily of transcription factors also has a role in mammary gland development and the potential role of this transcription factor in modulating mammaryepithelial apoptosis and involution of the mammarygland is discussed.
Abstract: A number of transcription factors have beenidentified as regulators of mammary development,including Stat5 and C/EBPβ (1-3). In this review wesummarize evidence which suggests that the NF-κBfamily of transcription factors also has a role inmammary gland development. NF-κB was originallydescribed as a mediator of inflammatory reactions andcellular responses to viral pathogens. More recently it has been shown to possess an anti-apoptoticeffect in a variety of cell types by regulatingapoptosis-related genes. In the light of this functionin other tissues, and the observation that aberrant activation of NF-κB can be associatedwith mammary tumors, we discuss the potential role ofthis transcription factor in modulating mammaryepithelial apoptosis and involution of the mammarygland.
TL;DR: The effects of HGF/SF on primary mouse and human mammary epithelial cells in vitro are discussed, detailing the individual response of the two epithelial sub-population of cells which comprise this organ.
Abstract: HGF/SF is a multifunctional cytokine which through binding to its cellular receptor, c-MET, can elicit mitogenic, morphogenic and motogenic responses in target cells Expression of HGF/SF and c-MET has been shown to be critical in early embryogenesis affecting development of many organs and tissues The effects of HGF/SF4 on established human and mouse mammary cell lines have previously been reported This review describes the source and targets for HGF/SF in both human and mouse mammary tissue and discusses the effects of HGF/SF on primary mouse and human mammary epithelial cells in vitro, detailing the individual response of the two epithelial sub-population of cells which comprise this organ Additionally, the effects of HGF/SF overexpression on mouse mammary gland development in vivo, are summarized
TL;DR: A positive relation between maternalfatness and milk fat is evident in both well- nourished and under-nourished women when appropriatemethodologies have been used, and themechanism for the relationship between body fat and milkfat is a fertile field for additional investigation.
Abstract: The relationship between maternal dietary intakes of energy or fat maternal body composition and the milk fat concentration is an important element in understanding the role of breast-milk in infant nutrition. In most studies in both developing and developed countries, no relation between maternal energy intake and milk fat content was observed. In only one published study, in which maternal fat intake comprised a very low 5% of calories, was a short term reduction in milk lipid observed in some subjects. On the other hand, a positive relation between maternal fatness and milk fat is evident in both well-nourished and under-nourished women when appropriate methodologies have been used. Low milk fat concentrations are associated with higher milk volumes probably because infant demand determines milk intake, compensating, at least partially, for low milk fat. No impairment of infant growth was associated with low milk fat, in studies where it has been measured. The mechanism for the relationship between body fat and milk fat is a fertile field for additional investigation.
TL;DR: Because of declining milk zincconcentrations and intake, zinc status in exclusively breastfed infants is likely to become marginal beyond 6 months of age, and may become suboptimal for some infants if exclusive breastfeeding continues.
Abstract: Zinc is a micronutrient which is critical to normal growth and development. Zinc concentrations in human milk decline sharply during the early months post partum, regardless of maternal zinc intake. Milk zinc concentrations do not increase in response to increased maternal zinc intake if maternal zinc status is adequate. The mechanism of zinc secretion into milk is not fully understood. A mutation in the gene for a zinc transporter protein may account for abnormally low milk zinc concentrations associated with severe zinc deficiency in breastfed infants. The zinc requirements of breastfed infants are generally met with exclusive breastfeeding through 5-6 months of age, due to the favorable bioavailability of the zinc in human milk. Because of declining milk zinc concentrations and intake, zinc status in exclusively breastfed infants is likely to become marginal beyond 6 months of age, and may become suboptimal for some infants if exclusive breastfeeding continues. The choice of complementary foods is important to maintain adequate zinc status in breastfed infants after 6 months.
TL;DR: The role of retinoid receptors and their receptors in the treatment and prevention of breast cancer is discussed, and several retinoids, including all trans retinoic acid and 9-cis retinic acid, have been shown to havemodest activity in the Treatment of Breast cancer, and these agents are now in clinical trials in combination withcytotoxic agents and anti-estrogens.
Abstract: Retinoids are vitamin A-related compounds thathave been found to prevent cancer in animals and humans.In this review, we discuss the role of retinoids andtheir receptors in the treatment and prevention of breast cancer. The retinoid receptors areexpressed in normal and malignant breast cells, and arecritical for normal development. In breast cells, whenbound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation.The mechanism by which retinoids inhibit breast cellgrowth has not been completely elucidated, however,retinoids have been shown to affect multiple signal transduction pathways, including IGF-,TGFβ-, and AP-1-dependent pathways. Retinoids havealso been shown to suppress the growth and prevent thedevelopment of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treatedrats and in transgenic mice, and inhibit the growth oftransplanted breast tumors. These promising preclinicalresults have provided the rationale to test retinoids in clinical trials for the treatment andprevention of breast cancer. Several retinoids,including all trans retinoic acid and9-cis retinoic acid, have been shown to havemodest activity in the treatment of breast cancer, and theseagents are now in clinical trials in combination withcytotoxic agents and anti-estrogens. Another retinoid,4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggestthat 4-HPR may suppress breast cancer development inpremenopausal women. Future clinical trials will focuson testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic andpreventive efficacy.
TL;DR: Localization adjacent to the presumptive luminas suggests that this process functions to sculpt the lumina of the subtending duct in the pubertal mouse mammarygland and members of the Bcl-2family of apoptosis regulatory molecules appear to have some role in regulating apoptosis in the terminal endbud.
Abstract: Ductal development in the pubertal mouse mammary gland is characterized by dramatic morphological changes in the epithelium driven by proliferation of cap and body cells in the terminal endbuds Recent experiments revealed a coincident and abundant apoptosis in the body cells of these structures The cells undergoing apoptosis are occasionally restricted to defined regions within the terminal endbud Localization adjacent to the presumptive lumina suggests that this process functions to sculpt the lumina of the subtending duct Members of the Bcl-2 family of apoptosis regulatory molecules; Bcl-2 and Bcl-x, appear to have some role in regulating apoptosis in the terminal endbud Other possible signals which could regulate this developmental process and a model are presented
TL;DR: The available data suggest that the quality of survival of premature infants can be improved, both inthe short-term and long-term, through the feeding of human milk.
Abstract: As the rate of survival of premature infants isincreasing, more attention is necessarily focused onimproving the quality of survival through optimalnutritional management. The nutritional needs of the premature infant are greater than at any othertime in the life cycle. The benefits of human milk forterm infants are well known. Emerging data suggest thathuman milk may especially benefit the premature infant. The human milk-fed premature infant mayexperience improved health (such as lower rates ofinfection and necrotizing enterocolitis),gastrointestinal function, and neurodevelopment. Thesefactors may outweigh the concerns about adequategrowth, nutrient accretion, and biochemical indices ofnutritional status attributed to the lower nutrientcontent of human milk compared with preterm formula.Some of the nutritional concerns may be met by theuse of multinutrient supplements during the time infantsreceive tube-feeding, generally the time prior toattaining complete oral feeding in-hospital. The available data suggest that the quality ofsurvival of premature infants can be improved, both inthe short-term and long-term, through the feeding ofhuman milk.
TL;DR: A series of monoclonalantibodies directed against the EGF(ErbB1) receptor and the closely related HER2/Neu( ErbB2) receptor are currently under evaluation, and compounds that inhibit receptortyrosine kinases have shown significant preclinicalactivity and are currently being evaluated in the clinic.
Abstract: Breast carcinomas express high levels of ErbB receptors and their ligands, and their overexpression has been associated with a more aggressive clinical behavior. For these reasons therapies directed at these receptors have the potential to be useful anti-cancer treatments. A series of monoclonal antibodies (MAbs)3 directed against the EGF (ErbB1) receptor and the closely related HER2/Neu (ErbB2) receptor are currently under evaluation. These MAbs have shown promising preclinical activity and "chimeric" and "humanized" MAbs have been produced in order to obviate the problem of host immune reactions. These antibodies are currently being tested in clinical trials either alone or in combination with chemotherapeutic agents. Clinical activity with one of these antibodies, trastuzumab, a humanized anti-ErbB2 MAb, has been documented in patients with breast cancer in a series of clinical trials and has recently been approved for the therapy of patients with metastatic ErbB2 overexpressing breast cancer. In addition to antibodies, compounds that inhibit receptor tyrosine kinases have shown significant preclinical activity and are currently being evaluated in the clinic.