-
Journal of Mammary Gland Biology and... Jun 2013Most mammals develop their mammary glands in pairs of which the two counterparts are symmetrically displaced away from the ventral midline. Based on this symmetry and... (Review)
Review
Most mammals develop their mammary glands in pairs of which the two counterparts are symmetrically displaced away from the ventral midline. Based on this symmetry and the same functional outcome as a milk-producing organ, the mammary glands are easily presumed to be mere copies of one another. Based on our analysis of published data with inclusion of new results related to mammary development and pathology in mice, we argue that this presumption is incorrect: Between and within pairs, mammary glands differ from one another, and tumor incidence and biology depend on the position along the anterior-posterior and the left-right axis as well. This insight has implications for experimental designs with mouse models and for data extrapolation between mammary glands within and between species. We suggest that improved documentation of location-specific mammary gland features will lead to more insights into the molecular mechanisms of mammary gland development and cancer biology in both mice and humans.
Topics: Animals; Breast Neoplasms; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mammary Neoplasms, Experimental
PubMed: 23666389
DOI: 10.1007/s10911-013-9287-3 -
Biochimica Et Biophysica Acta.... Sep 2022
Topics: Humans; Mammary Glands, Human
PubMed: 35523399
DOI: 10.1016/j.bbamcr.2022.119283 -
International Journal of Molecular... Jun 2018Since seminal descriptions of signal transducer and activator of transcription 3 (STAT3) as a signal transducer and transcriptional regulator, which is most usually... (Review)
Review
Since seminal descriptions of signal transducer and activator of transcription 3 (STAT3) as a signal transducer and transcriptional regulator, which is most usually activated by phosphorylation of a specific tyrosine residue, a staggering wealth of research has delineated the key role of this transcription factor as a mediator of mammary gland postlactational regression (involution), and paradoxically, a pro-survival factor in breast cancer and some breast cancer cell lines. STAT3 is a critical regulator of lysosomal-mediated programmed cell death (LM-PCD) during mammary gland involution, where uptake of milk fat globules, and consequent high levels of free fatty acids, cause permeabilisation of lysosomal vesicle membranes, in turn leading to cathepsin protease leakage and cell death. A recent proteomic screen of STAT3-induced changes in lysosomal membrane protein components has highlighted wide-ranging effects of STAT3, which may coordinate LM-PCD via the stimulation of endocytosis, intracellular trafficking, and lysosome biogenesis. In parallel, STAT3 regulates the acute phase response during the first phase of involution, and it contributes to shaping the pro-tumourigenic 'wound healing' signature of the gland during the second phase of this process. STAT3 activation during involution is important across species, although some differences exist in the progression of involution in dairy cows. In breast cancer, a number of upstream regulators can lead to STAT3 activation and the effects of phosphorylation of STAT3 are equally wide-ranging. Recent studies have implicated microRNAs in some regulatory pathways. In this review, we will examine the multifaceted role of STAT3 in mammary gland involution and tumourigenesis, incorporating a review of these fundamental processes in tandem with a discussion of recent developments in this field.
Topics: Animals; Biomarkers; Breast Neoplasms; Cell Transformation, Neoplastic; Cellular Microenvironment; Female; Gene Expression Regulation; Humans; Mammary Glands, Human; STAT3 Transcription Factor; Signal Transduction
PubMed: 29875329
DOI: 10.3390/ijms19061695 -
Cold Spring Harbor Perspectives in... Jan 2011Cells of the mammary gland are in intimate contact with other cells and with the extracellular matrix (ECM), both of which provide not only a biochemical context, but a... (Review)
Review
Cells of the mammary gland are in intimate contact with other cells and with the extracellular matrix (ECM), both of which provide not only a biochemical context, but a mechanical context as well. Cell-mediated contraction allows cells to sense the stiffness of their microenvironment, and respond with appropriate mechanosignaling events that regulate gene expression and differentiation. ECM composition and organization are tightly regulated throughout development of the mammary gland, resulting in corresponding regulation of the mechanical environment and proper tissue architecture. Mechanical regulation is also at play during breast carcinoma progression, as changes in ECM deposition, composition, and organization accompany breast carcinoma. These changes result in stiffer matrices that activate mechanosignaling pathways and thereby induce cell proliferation, facilitate local tumor cell invasion, and promote progression. Thus, understanding the role of forces in the mammary gland is crucial to understanding both normal developmental and pathological processes.
Topics: Animals; Biomechanical Phenomena; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Collagen; Extracellular Matrix; Female; Fibronectins; Focal Adhesions; Gene Expression Regulation; Humans; Mammary Glands, Human; Mechanotransduction, Cellular
PubMed: 20980442
DOI: 10.1101/cshperspect.a003228 -
Biochimica Et Biophysica Acta.... Jan 2022Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known... (Review)
Review
Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known about how milk is produced and how it is ejected from the lumen of mammary alveoli and ducts. This review focuses on the latter. We discuss how a relatively small number of basal cells, wrapping around each alveolar unit, contract to forcibly expel milk from the alveolar lumen. We consider how individual basal cells coordinate their activity, the fate of these cells at the end of lactation and avenues for future deliberation and exploration.
Topics: Animals; Cell Plasticity; Epithelial Cells; Female; Humans; Lactation; Mammary Glands, Human
PubMed: 34653580
DOI: 10.1016/j.bbamcr.2021.119159 -
Journal of Mammary Gland Biology and... Jan 2023The extracellular matrix (ECM) is biochemically and biomechanically important for the structure and function of the mammary gland, which undergoes vast structural...
The extracellular matrix (ECM) is biochemically and biomechanically important for the structure and function of the mammary gland, which undergoes vast structural changes throughout pubertal and reproductive development. Although hyaluronan (HA) is a ubiquitous glycosaminoglycan (GAG) of the mammary gland ECM, extensive characterization of HA deposition in the mammary gland is lacking. Understanding physiologic HA metabolism is critical as this tightly controlled system is often hijacked in cancer. In the current studies, we characterize HA regulation throughout mammary gland development to better understand subsequent dysregulation of HA in mammary tumors. Using immunofluorescence (IF) imaging, we demonstrate that organized HA-rich septa exist in the mammary gland stroma throughout puberty, pregnancy, and involution. Furthermore, we find heterogeneous HA deposition within two murine models of breast cancer. Using cell specific isolation techniques, we characterize expression of genes associated with HA binding, synthesis, and degradation within EpCAM + epithelial cells, CD90.2 + fibroblasts, and F4/80 + macrophages isolated from mammary glands and tumors. Most notably, we identify elevated levels of the hyaluronidases Hyal1 and Hyal2 in tumor-association macrophages (TAMs), suggesting a role for TAM-mediated turnover of HA in the tumor microenvironment (TME). Gene expression is supported functionally by in vitro experiments in which macrophages treated with tumor-cell conditioned media exhibit increased hyaluronidase activity. These findings link TAMs to the direct degradation of HA within the TME of mammary tumors, which has negative implications for patient survival.
Topics: Pregnancy; Female; Mice; Humans; Animals; Hyaluronic Acid; Mammary Glands, Human; Extracellular Matrix; Macrophages; Mammary Neoplasms, Animal; Tumor Microenvironment
PubMed: 36723776
DOI: 10.1007/s10911-023-09528-y -
Journal of Mammary Gland Biology and... Mar 2010Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression... (Review)
Review
Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conformation initiated by DNA methylation, histone variants, post-translational modifications of histones, non-histone chromatin proteins, and non-coding RNAs. Epigenetics plays a key role in development. However, very little is known about its role in the developing mammary gland or how it might integrate the many signalling pathways involved in mammary gland development and function that have been discovered during the past few decades. An inverse relationship between marks of closed (DNA methylation) or open chromatin (DnaseI hypersensitivity, certain histone modifications) and milk protein gene expression has been documented. Recent studies have shown that during development and functional differentiation, both global and local chromatin changes occur. Locally, chromatin at distal regulatory elements and promoters of milk protein genes gains a more open conformation. Furthermore, changes occur both in looping between regulatory elements and attachment to nuclear matrix. These changes are induced by developmental signals and environmental conditions. Additionally, distinct epigenetic patterns have been identified in mammary gland stem and progenitor cell sub-populations. Together, these findings suggest that epigenetics plays a role in mammary development and function. With the new tools for epigenomics developed in recent years, we now can begin to establish a framework for the role of epigenetics in mammary gland development and disease.
Topics: Animals; Breast Neoplasms; Cell Differentiation; Chromatin; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Histones; Humans; Mammary Glands, Animal; Mammary Glands, Human; RNA, Untranslated; Stem Cells; Transcription Factors; Transcription, Genetic
PubMed: 20157770
DOI: 10.1007/s10911-010-9170-4 -
Cells Oct 2021Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances... (Review)
Review
Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.
Topics: Adaptation, Physiological; Breast Neoplasms; Disease Progression; Female; Humans; Mammary Glands, Human; Morphogenesis; Stress, Physiological
PubMed: 34685621
DOI: 10.3390/cells10102641 -
Breast Cancer Research : BCR 2009Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of... (Review)
Review
Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.
Topics: Androgens; Breast Neoplasms; Female; Humans; Mammary Glands, Human
PubMed: 19889198
DOI: 10.1186/bcr2413 -
Cells Oct 2022The mammary gland is a unique organ with the ability to undergo repeated cyclic changes throughout the life of mammals. Among domesticated livestock species, ruminants... (Review)
Review
The mammary gland is a unique organ with the ability to undergo repeated cyclic changes throughout the life of mammals. Among domesticated livestock species, ruminants (cattle and buffalo) constitute a distinct class of livestock species that are known milk producers. Cattle and buffalo contribute to 51 and 13% of the total milk supply in the world, respectively. They also play an essential role in the development of the economy for farming communities by providing milk, meat, and draft power. The development of the ruminant mammary gland is highly dynamic and multiphase in nature. There are six developmental stages: embryonic, prepubertal, pubertal, pregnancy, lactation, and involution. There has been substantial advancement in our understanding of the development of the mammary gland in both mouse and human models. Until now, there has not been a thorough investigation into the molecular processes that underlie the various stages of cow udder development. The current review sheds light on the morphological and molecular changes that occur during various developmental phases in diverse species, with a particular focus on the cow udder. It aims to explain the physiological differences between cattle and non-ruminant mammalian species such as humans, mice, and monkeys. Understanding the developmental biology of the mammary gland in molecular detail, as well as species-specific variations, will facilitate the researchers working in this area in further studies on cellular proliferation, differentiation, apoptosis, organogenesis, and carcinogenesis. Additionally, in-depth knowledge of the mammary gland will promote its use as a model organ for research work and promote enhanced milk yield in livestock animals without affecting their health and welfare.
Topics: Pregnancy; Female; Cattle; Animals; Mice; Humans; Buffaloes; Mammary Glands, Human; Mammary Glands, Animal; Lactation; Milk
PubMed: 36291191
DOI: 10.3390/cells11203325