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Disease Models & Mechanisms Mar 2022RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in...
RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in specific developmental stages. We found that RET is differentially expressed during mouse mammary gland development: RET is present in lactation and its expression dramatically decreases in involution, the period during which the lactating gland returns to a quiescent state after weaning. Based on epidemiological and pre-clinical findings, involution has been described as tumor promoting. Using the Ret/MTB doxycycline-inducible mouse transgenic system, we show that sustained expression of RET in the mammary epithelium during the post-lactation transition to involution is accompanied by alterations in tissue remodeling and an enhancement of cancer potential. Following constitutive Ret expression, we observed a significant increase in neoplastic lesions in the post-involuting versus the virgin mammary gland. Furthermore, we show that abnormal RET overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and, using RNA sequencing, an acute-phase inflammatory signature. Our results demonstrate that RET overexpression negatively affects the normal post-lactation transition.
Topics: Animals; Female; Humans; Lactation; Mammary Glands, Animal; Mammary Glands, Human; Mice; Neoplasms; Proto-Oncogene Proteins c-ret; STAT3 Transcription Factor
PubMed: 35044452
DOI: 10.1242/dmm.049286 -
Journal of Mammary Gland Biology and... Sep 2018Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the...
Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the secretion and potential physiological function of non-pathological EVs secreted by polarized normal mammary epithelial cells. Using a transwell system to allow formation of epithelial polarity and EV collection from the apical versus basolateral compartments, we found that impaired secretion of EVs by knockdown of RAB27A or RAB27B suppressed the establishment of mammary epithelial polarity, and that addition of apical but not basolateral EVs suppressed epithelial polarity in a dose-dependent manner. This suggests that apical EV secretion contributes to epithelial polarity, and a possible mechanism is through removal of certain intracellular molecules. In contrast, basolateral but not apical EVs promoted migration of mammary epithelial cells in a motility assay. The protein contents of apical and basolateral EVs from MCF10A and primary human mammary epithelial cells were determined by mass spectrometry proteomic analysis, identifying apical-EV-enriched and basolateral-EV-enriched proteins that may contribute to different physiological functions. Most of these proteins differentially secreted by normal mammary epithelial cells through polarized EV release no longer showed polarized secretion in MCF10A-derived transformed epithelial cells. Our results suggest an essential role of EV secretion in normal mammary epithelial polarization and distinct protein contents and functions in apical versus basolateral EVs secreted by polarized mammary epithelia.
Topics: Cell Line; Cell Line, Tumor; Cell Movement; Cell Polarity; Epithelial Cells; Epithelium; Extracellular Vesicles; Female; Humans; Mammary Glands, Human; Proteomics; rab GTP-Binding Proteins
PubMed: 29968174
DOI: 10.1007/s10911-018-9402-6 -
Revista Chilena de Pediatria Apr 2018The mammary gland and maternal milk are the product of millions of years of evolution that resul ted in an optimal composition that sustains the growth and development... (Review)
Review
The mammary gland and maternal milk are the product of millions of years of evolution that resul ted in an optimal composition that sustains the growth and development of newborns and infants. Maternal milk supports the growth, adaptation and survival of this immature organism. Recent studies have detected 1606 different proteins in human milk, most of them synthesized in the acini of the glandular tissue while others originate from distant organs such as the lymphoid tissue and the digestive tract. Maternal milk enzymes modify its proteins and liberate peptides with antimicrobial, antihypertensive or stimulatory activities. This proteolytic activity occurs at specific sites in peptide chains. To prevent the extemporaneous activation of these proteolytic enzymes, that would result in inflammatory processes, maternal milk also contains inhibitory peptides that together with the stimulatory peptides conform a complex regulatory system. Some enzymes in maternal milk main tain their activity in the gastrointestinal tract of infants and compensate for the decreased activity of digestive tract enzymes in newborns. Thus, the milk enterokynase stimulates the release of pancreatic proteases as it induces the liberation of cholecystokynin/pancreozymin. The bile salt-activated lipase of human milk is activated in the duodenum by the infants' bile salts and partially compensates for the low levels of pancreatic lipase in newborns. These milk enzymes probably contribute to the nutrition of premature infants as they increase the availability of amino acids and peptides in their upper gastrointestinal tract; furthermore, as their intestinal epithelium is more permeable to peptides and partially digested protein this may help induce immune tolerance. The most relevant issues in the physiology and composition of the maternal milk are presented in this review.
Topics: Biological Evolution; Humans; Mammary Glands, Human; Milk Proteins; Milk, Human; Proteome
PubMed: 29799897
DOI: 10.4067/S0370-41062018000200261 -
Viruses Oct 2019Zika virus (ZIKV) belongs to the large category of arboviruses. Surprisingly, several human-to-human transmissions of ZIKV have been notified, either following sexual...
Zika virus (ZIKV) belongs to the large category of arboviruses. Surprisingly, several human-to-human transmissions of ZIKV have been notified, either following sexual intercourse or from the mother to fetus during pregnancy. Importantly, high viral loads have been detected in the human breast milk of infected mothers, and the existence of breastfeeding as a new mode of mother-to-child transmission of ZIKV was recently hypothesized. However, the maternal origin of infectious particles in breast milk is currently unknown. Here, we show that ZIKV disseminates to the mammary glands of infected mice after both systemic and local exposure with differential kinetics. Ex vivo, we demonstrate that primary human mammary epithelial cells were sensitive and permissive to ZIKV infection in this study. Moreover, by using in vitro models, we prove that mammary luminal- and myoepithelial-phenotype cell lines are both able to produce important virus progeny after ZIKV exposure. Our data suggest that the dissemination of ZIKV to the mammary glands and subsequent infection of the mammary epithelium could be one mechanism of viral excretion in human breast milk.
Topics: Animals; Cell Line; Epithelial Cells; Female; Humans; Infectious Disease Transmission, Vertical; Mammary Glands, Human; Mice; Milk, Human; Pregnancy; RNA, Viral; Viral Load; Viral Tropism; Virus Replication; Zika Virus
PubMed: 31619008
DOI: 10.3390/v11100950 -
Nucleic Acids Research Feb 2016Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most...
Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development and function. We report that the ubiquitously expressed Stat5a/b locus is subject to additional lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitivity, H3K27 acetylation and binding by GR, NFIB, ELF5 and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that contributes to the remarkable abundance of STAT5 and, in turn, to the efficacy of STAT5-dependent mammary physiology.
Topics: Animals; Base Sequence; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Enhancer Elements, Genetic; Female; Humans; Mammary Glands, Human; Mice; Molecular Sequence Data; STAT5 Transcription Factor
PubMed: 26446995
DOI: 10.1093/nar/gkv999 -
Archives of Histology and Cytology Dec 2004Steroid sex hormones (17beta-estradiol, testosterone, dihydrotestosterone, and progesterone) and aryl hydrocarbons such as the dioxins regulate epithelial proliferation... (Review)
Review
Steroid sex hormones (17beta-estradiol, testosterone, dihydrotestosterone, and progesterone) and aryl hydrocarbons such as the dioxins regulate epithelial proliferation and secretory protein production and differentiation in their respective target organs in male and female urogenital tracts and mammary glands. Recent evidence has demonstrated that stromal-epithelial interactions are critical for mediating the effects of these molecules on epithelial cells. Our results have indicated that estradiol, testosterone, progesterone, and dioxin regulate epithelial proliferation (stimulation or inhibition) via paracrine mechanisms requiring the appropriate receptor in the stroma. The androgen receptor (AR), estrogen receptor alpha (ERalpha), progesterone receptor (PR), or aryl hydrocarbon receptor (AhR) in the epithelium are neither necessary nor sufficient for the regulation of epithelial proliferation. Moreover, during prostatic development, signaling through the stromal AR is required to induce prostatic epithelial identity, ductal morphogenesis and glandular differentiation. Epithelial functional differentiation is regulated in the prostate, uterus, and vagina via AR (prostate) and ERalpha(uterus and vagina). In these organs both epithelial and stromal steroid receptors are required for steroidal regulation of certain aspects of epithelial differentiation such as epithelial secretory protein production in the uterus and epithelial cornification in the vagina and prostate (squamous metaplasia). The mechanistic basis of these stromal-epithelial interactions is poorly understood, but growth factors appear to be mediators of these cell-cell interactions.
Topics: Animals; Cell Differentiation; Cell Proliferation; Epithelial Cells; Female; Humans; Male; Mammary Glands, Animal; Mammary Glands, Human; Models, Biological; Paracrine Communication; Prostate; Steroids; Stromal Cells; Uterus; Vagina
PubMed: 15781983
DOI: 10.1679/aohc.67.417 -
American Society of Clinical Oncology... 2013The radiographic appearance of the breast on mammography varies among women, and reflects variations in breast tissue composition and the different X-ray attenuation... (Review)
Review
The radiographic appearance of the breast on mammography varies among women, and reflects variations in breast tissue composition and the different X-ray attenuation characteristics of these tissues. Fat is radiologically lucent and appears dark on a mammogram. Connective and epithelial tissues are radiologically dense and appear light. These variations in appearance are commonly described as the percentage of the breast image that is radiologically dense, or as percent mammographic density (PMD). There is now extensive evidence that PMD is a risk factor for breast cancer, with a 4- to 6-fold gradient in risk between women with 75% or more PMD compared with those with 10% or less. However, the accuracy of risk prediction in individual women is modest. The extent of PMD is associated inversely with greater age, parity, and weight, and is reduced by the menopause and by tamoxifen. PMD is positively associated with greater height, a family history of breast cancer, and is increased by combined hormone therapy. The relative risk associated with density is substantially larger than the relative risk of breast cancer associated with a family history of the disease or any of the menstrual and reproductive risk factors. It is estimated that the risks of breast cancer attributable to density of 50% or more may be 16% for all breast cancers. Although combined hormone therapy and tamoxifen respectively increase a decrease both PMD and breast cancer risk, there is as yet insufficient evidence to use PMD as a surrogate marker for breast cancer.
Topics: Adipose Tissue; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Breast; Breast Density; Breast Neoplasms; Cohort Studies; Connective Tissue; Disease Susceptibility; Epithelium; Female; Humans; Mammary Glands, Human; Mammography; Menopause; Middle Aged; Risk
PubMed: 23714456
DOI: 10.14694/EdBook_AM.2013.33.e57 -
Breast Cancer Research : BCR Jul 2021We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples.
BACKGROUND
We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples.
METHODS
This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study and Nurses' Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors.
RESULTS
As compared to parous women, nulliparous women had a smaller percentage of epithelium (β = - 0.26, 95% confidence interval [CI] - 0.41, - 0.11) and fat (β = - 0.34, 95% CI - 0.54, - 0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (β per child = - 0.01, 95% CI - 0.02, - 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β = - 0.30, 95% CI - 0.54, - 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma.
CONCLUSIONS
Our findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.
Topics: Adipose Tissue; Adult; Breast; Breast Diseases; Breast Neoplasms; Epithelium; Female; Humans; Middle Aged; Reproductive History; Risk Factors; Stromal Cells
PubMed: 34225771
DOI: 10.1186/s13058-021-01447-2 -
Journal of Mammary Gland Biology and... Jun 2008The ErbB receptor tyrosine kinase family has often been associated with increased growth of breast epithelial cells, as well as malignant transformation and progression.... (Review)
Review
The ErbB receptor tyrosine kinase family has often been associated with increased growth of breast epithelial cells, as well as malignant transformation and progression. In contrast, ErbB4/HER4 exhibits unique attributes from a two step proteolytic cleavage which releases an 80 kilodalton, nuclear localizing, tyrosine kinase to a signal transduction mechanism that slows growth and stimulates differentiation of breast cells. This review provides an overview of ErbB4/HER4 in growth and differentiation of the mammary epithelium, including its physiologic role in development, the contrasting growth inhibition/tumor suppression and growth acceleration of distinct ErbB4/HER4 isoforms and a description of the unique cell cycle regulated pattern of nuclear HER4 ubiquitination and destruction.
Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Cell Differentiation; ErbB Receptors; Female; Growth Inhibitors; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Protein Isoforms; Receptor, ErbB-4; Signal Transduction; Tumor Cells, Cultured
PubMed: 18437540
DOI: 10.1007/s10911-008-9080-x -
Breast Cancer Research : BCR 2007Int6 has been shown to be an interactive participant with the protein translation initiation complex eIF3, the COP9 signalosome and the regulatory lid of the 26S...
INTRODUCTION
Int6 has been shown to be an interactive participant with the protein translation initiation complex eIF3, the COP9 signalosome and the regulatory lid of the 26S proteasome. Insertion of mouse mammary tumor virus into the Int6 locus creates a C-terminally truncated form of the protein. Expression of the truncated form of Int6 (Int6sh) in stably transfected human and mouse mammary epithelial cell lines leads to cellular transformation. In addition, decreased expression of Int6/eIF3e is observed in approximately one third of all human breast carcinomas.
METHODS
To validate that Int6sh has transforming activity in vivo, a transgenic mouse model was designed using the whey acidic protein (Wap) promoter to target expression of truncated Int6 to differentiating alveolar epithelial cells in the mammary gland. Microarray analyses were performed on normal, premalignant and malignant WapInt6sh expressing tissues.
RESULTS
Mammary tumors developed in 42% of WapInt6sh heterozygous parous females at an average age of 18 months. In WapInt6sh mice, the contralateral mammary glands from both tumorous and non-tumorous tissues contained widespread focal alveolar hyperplasia. Only 4% of WapInt6sh non-breeding females developed tumors by 2 years of age. The Wap promoter is active only during estrus in the mammary tissue of cycling non-pregnant mice. Microarray analyses of mammary tissues demonstrated that Int6sh expression in the alveolar tissue altered the mammary transcriptome in a specific manner that was detectable even in the first pregnancy. This Int6sh-specific transcriptome pattern subsequently persisted in both the Int6sh-expressing alveolar hyperplasia and mammary tumors. These observations are consistent with the conclusion that WapInt6sh-expressing alveolar cells survive involution following the cessation of lactation, and subsequently give rise to the mammary tumors that arise in aging multiparous females.
CONCLUSION
These observations provide direct in vivo evidence that mammary-specific expression of the Int6sh truncation leads to persistence of alveolar hyperplasia with the accompanying increased predisposition to mammary tumorigenesis.
Topics: Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Epithelium; Eukaryotic Initiation Factor-3; Female; Gene Expression Profiling; Humans; Hyperplasia; Male; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Milk Proteins; Oligonucleotide Array Sequence Analysis; Plasmids; Pregnancy; Promoter Regions, Genetic; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Sequence Deletion; Transfection; Tumor Cells, Cultured
PubMed: 17626637
DOI: 10.1186/bcr1742