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المؤلفون: Madeleine Holm, Kumari Ubhayasekera, Marike Gabrielson, Mikael Eriksson, Kamila Czene, Elina Hardell, Magnus Bäcklund, Shadi Azam, Per Hall, Jonas Bergquist
المصدر: Breast Cancer Research, Vol 22, Iss 1, Pp 1-12 (2020)
Breast Cancer Research : BCRمصطلحات موضوعية: medicine.medical_treatment, 0302 clinical medicine, Sex hormone-binding globulin, Adrenal Cortex Hormones, Risk Factors, Testosterone, Breast, Prospective Studies, skin and connective tissue diseases, Mammographic density, Progesterone, Breast Density, biology, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Postmenopause, Risk factors for breast cancer, 030220 oncology & carcinogenesis, Female, Mammography, Research Article, medicine.medical_specialty, medicine.drug_class, Reproduktionsmedicin och gynekologi, Breast Neoplasms, Peptide hormone, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, Obstetrics, Gynecology and Reproductive Medicine, Internal medicine, medicine, Humans, Cancer och onkologi, Progestogen, business.industry, Estrogens, Mammographic density change, Androgen, medicine.disease, Hormones, Prolactin, Endocrinology, Premenopause, Cancer and Oncology, Plasma hormones, biology.protein, business, Hormone
الوصف: BackgroundMammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm2) and annual MD change (cm2/year).MethodsThis study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time.ResultsGreater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm2per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm2), oesterone sulphate (+ 1.42 cm2), prolactin (+ 2.11 cm2) and SHBG (+ 4.18 cm2), and inversely associated with 11-deoxycortisol (− 1.33 cm2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was − 0.8 cm2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was − 0.96 cm2and − 1.16 cm2lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations.ConclusionsOur results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.
وصف الملف: application/pdf
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4c964de8cafe71ceb987bffba62e6778
http://link.springer.com/article/10.1186/s13058-020-01332-4 -
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المؤلفون: Hari Singhal, J. Julie Kim, MiRan Choi, Batzaya Davaadelger, Susan E. Clare, Seema A. Khan
المصدر: Breast Cancer Research : BCR
Breast Cancer Research, Vol 21, Iss 1, Pp 1-13 (2019)مصطلحات موضوعية: Gene Expression, Breast Neoplasms, Biology, lcsh:RC254-282, Breast organoid, Progesterone receptor, Tissue Culture Techniques, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, Selective progesterone receptor modulator, Organoid, medicine, Humans, Mammary Glands, Human, skin and connective tissue diseases, Progesterone, 030304 developmental biology, Telapristone Acetate, 0303 health sciences, BRCA1 Protein, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, BRCA1, medicine.disease, Immunohistochemistry, Hormones, Extracellular Matrix, Organoids, Hormone receptor, 030220 oncology & carcinogenesis, Mutation, Cancer research, TPA, Female, Biomarkers, Research Article, Extracellular matrix organization, Hormone
الوصف: BackgroundWomen, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. While BRCA1 carriers frequently develop triple-negative, basal-like, aggressive breast tumors, hormone signaling is important in the genesis of BRCA1 mutant breast cancers. We investigated the hormone response in BRCA1-mutated benign breast tissue using an in vitro organoid system.MethodsScaffold-free, multicellular human breast organoids generated from benign breast tissues from non-carrier or BRCA1 mutation carriers were treated in vitro with a stepwise menstrual cycle hormone regimen of estradiol (E2) and progesterone (P4) over the course of 28 days.ResultsBreast organoids exhibited characteristics of the native breast tissue, including expression of hormone receptors, collagen production, and markers of luminal and basal epithelium, and stromal fibroblasts. RNA sequencing analysis revealed distinct gene expression in response to hormone treatment in the non-carrier and BRCA1-mutated organoids. The selective progesterone receptor modulator, telapristone acetate (TPA), was used to identify specifically PR regulated genes. Specifically, extracellular matrix organization genes were regulated by E2+P4+TPA in the BRCA1-mutated organoids but not in the non-carrier organoids. In contrast, in the non-carrier organoids, known PR target genes such as the cell cycle genes were inhibited by TPA.ConclusionsThese data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system.
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المؤلفون: Vilde Drageset Haakensen, Elena Papaleo, Søren Brunak, Pavel Gromov, Anders Krogh, Francesco Russo, Irina Gromova, Thilde Terkelsen
المصدر: Terkelsen, T, Russo, F, Gromov, P, Haakensen, V D, Brunak, S, Gromova, I, Krogh, A & Papaleo, E 2020, ' Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration ', Breast Cancer Research, vol. 22, no. 1, 73 . https://doi.org/10.1186/s13058-020-01295-6
Breast Cancer Research, Vol 22, Iss 1, Pp 1-36 (2020)
Breast Cancer Research : BCRمصطلحات موضوعية: Interaction networks, Receptor, ErbB-2, Tumor grade, Triple Negative Breast Neoplasms, Biology, lcsh:RC254-282, Tumor-infiltrating lymphocytes, Metastasis, Transcriptome, 03 medical and health sciences, Gene target, Lymphocytes, Tumor-Infiltrating, Breast cancer, 0302 clinical medicine, miRNA families, microRNA, Biomarkers, Tumor, Tumor Microenvironment, medicine, Humans, Gene silencing, Gene Regulatory Networks, Triple-negative breast cancer, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Tumor interstitial fluid, Gene Expression Profiling, Cancer, Extracellular Fluid, Biomarker, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Co-expression analysis, MicroRNAs, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cancer research, Female, Neoplasm Grading, Receptors, Progesterone, TNBC, Research Article, Follow-Up Studies
الوصف: Background Studies on tumor-secreted microRNAs point to a functional role of these in cellular communication and reprogramming of the tumor microenvironment. Uptake of tumor-secreted microRNAs by neighboring cells may result in the silencing of mRNA targets and, in turn, modulation of the transcriptome. Studying miRNAs externalized from tumors could improve cancer patient diagnosis and disease monitoring and help to pinpoint which miRNA-gene interactions are central for tumor properties such as invasiveness and metastasis. Methods Using a bioinformatics approach, we analyzed the profiles of secreted tumor and normal interstitial fluid (IF) microRNAs, from women with breast cancer (BC). We carried out differential abundance analysis (DAA), to obtain miRNAs, which were enriched or depleted in IFs, from patients with different clinical traits. Subsequently, miRNA family enrichment analysis was performed to assess whether any families were over-represented in the specific sets. We identified dysregulated genes in tumor tissues from the same cohort of patients and constructed weighted gene co-expression networks, to extract sets of co-expressed genes and co-abundant miRNAs. Lastly, we integrated miRNAs and mRNAs to obtain interaction networks and supported our findings using prediction tools and cancer gene databases. Results Network analysis showed co-expressed genes and miRNA regulators, associated with tumor lymphocyte infiltration. All of the genes were involved in immune system processes, and many had previously been associated with cancer immunity. A subset of these, BTLA, CXCL13, IL7R, LAMP3, and LTB, was linked to the presence of tertiary lymphoid structures and high endothelial venules within tumors. Co-abundant tumor interstitial fluid miRNAs within this network, including miR-146a and miR-494, were annotated as negative regulators of immune-stimulatory responses. One co-expression network encompassed differences between BC subtypes. Genes differentially co-expressed between luminal B and triple-negative breast cancer (TNBC) were connected with sphingolipid metabolism and predicted to be co-regulated by miR-23a. Co-expressed genes and TIF miRNAs associated with tumor grade were BTRC, CHST1, miR-10a/b, miR-107, miR-301a, and miR-454. Conclusion Integration of IF miRNAs and mRNAs unveiled networks associated with patient clinicopathological traits, and underlined molecular mechanisms, specific to BC sub-groups. Our results highlight the benefits of an integrative approach to biomarker discovery, placing secreted miRNAs within a biological context.
وصف الملف: application/pdf
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المؤلفون: Andrea Ferreira-Gonzalez, Jessica Finlay-Schultz, J. Chuck Harrell, Kiran V. Paul, Scott A. Turner, Duncan Riley, Peter Kabos, Carol A. Sartorius, Britta M. Jacobsen
المصدر: Breast Cancer Research : BCR
Breast Cancer Research, Vol 22, Iss 1, Pp 1-12 (2020)مصطلحات موضوعية: Receptor, ErbB-2, Breast cancer subtypes, Cell, Cell Culture Techniques, Estrogen receptor, Breast Neoplasms, Mice, SCID, Biology, Oncogenomics, lcsh:RC254-282, Mice, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Cyclin D1, Mice, Inbred NOD, Cell Line, Tumor, medicine, Animals, Humans, skin and connective tissue diseases, 030304 developmental biology, 0303 health sciences, Fulvestrant, Gene Expression Profiling, Carcinoma, Ductal, Breast, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Breast cancer cell lines, Carcinoma, Lobular, Patient-derived xenografts, medicine.anatomical_structure, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cancer research, Heterografts, Female, Receptors, Progesterone, Estrogen receptor alpha, Tamoxifen, Research Article, medicine.drug
الوصف: Background Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics. Methods Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers. Results Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR−/low cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER− and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers. Conclusions These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.
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المؤلفون: Todd W. Miller, Arminja N. Kettenbach, Jonathan D. Marotti, Yue Wang, Youdinghuan Chen, Chao Cheng, Kenneth M. K. Mark, Brock C. Christensen, Lucas A. Salas
المصدر: Breast Cancer Research : BCR
Breast Cancer Research, Vol 21, Iss 1, Pp 1-13 (2019)مصطلحات موضوعية: Adult, Epigenomics, Genome instability, Support Vector Machine, DNA Copy Number Variations, DNA repair, Datasets as Topic, Breast Neoplasms, Biology, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Surgical oncology, BRCAness, medicine, Humans, Breast, Epigenetics, Homologous recombination, Promoter Regions, Genetic, skin and connective tissue diseases, Triple-negative breast cancer, Aged, DNA methylation, BRCA1 Protein, Precision medicine, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, BRCA1, medicine.disease, Survival Analysis, 3. Good health, Differentially methylated regions, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cancer research, CpG Islands, Female, Receptors, Progesterone, Research Article
الوصف: Background BRCA1-mutated cancers exhibit deficient homologous recombination (HR) DNA repair, resulting in extensive copy number alterations and genome instability. HR deficiency can also arise in tumors without a BRCA1 mutation. Compared with other breast tumors, HR-deficient, BRCA1-like tumors exhibit worse prognosis but selective chemotherapeutic sensitivity. Presently, patients with triple negative breast cancer (TNBC) who do not respond to hormone endocrine-targeting therapy are given cytotoxic chemotherapy. However, more recent evidence showed a similar genomic profile between BRCA1-deficient TNBCs and hormone-receptor-positive tumors. Characterization of the somatic alterations of BRCA1-like hormone-receptor-positive breast tumors as a group, which is currently lacking, can potentially help develop biomarkers for identifying additional patients who might respond to chemotherapy. Methods We retrained and validated a copy-number-based support vector machine (SVM) classifier to identify HR-deficient, BRCA1-like breast tumors. We applied this classifier to The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast tumors. We assessed mutational profiles and proliferative capacity by covariate-adjusted linear models and identified differentially methylated regions using DMRcate in BRCA1-like hormone-receptor-positive tumors. Results Of the breast tumors in TCGA and METABRIC, 22% (651/2925) were BRCA1-like. Stratifying on hormone-receptor status, 13% (302/2405) receptor-positive and 69% (288/417) triple-negative tumors were BRCA1-like. Among the hormone-receptor-positive subgroup, BRCA1-like tumors showed significantly increased mutational burden and proliferative capacity (both P
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المؤلفون: Dafne Ochoa, Harriet Leong, Gudmundur Thordarson, Raphael C. Guzman, Frank Talamantes, Nicole Slusher, Satyabrata Nandi, Lakshmanaswamy Rajkumar
المصدر: Breast Cancer Research
مصطلحات موضوعية: medicine.medical_specialty, endocrine system diseases, medicine.medical_treatment, Mammary gland, mitogen-activated protein kinase progesterone receptor, Estrogen receptor, Tumor initiation, Biology, Adenocarcinoma, Rats, Sprague-Dawley, 03 medical and health sciences, Insulin-like growth factor, mammary carcinogenesis, 0302 clinical medicine, estrogen receptor-α, Pregnancy, Internal medicine, Progesterone receptor, medicine, Animals, Insulin-Like Growth Factor I, reproductive and urinary physiology, 030304 developmental biology, Medicine(all), growth hormone/insulin-like growth factor-I, 0303 health sciences, Mammary tumor, Estrogen Receptor alpha, Mammary Neoplasms, Experimental, Methylnitrosourea, Carcinoma, Papillary, 3. Good health, Rats, Carcinoma, Ductal, Parity, Endocrinology, medicine.anatomical_structure, Receptors, Estrogen, 030220 oncology & carcinogenesis, Pregnancy, Animal, Female, Mitogen-Activated Protein Kinases, Estrogen receptor alpha, Hormone, Research Article
الوصف: Introduction Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. Methods Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. Results IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D1 and transforming growth factor-β3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous rats. Conclusion We argue that tumor initiation (transformation and fixation of mutations) may be similar in parous and age-matched virgin animals, suggesting that the main differences in tumor formation lie in differences in tumor progression caused by the altered hormonal environment associated with parity. Furthermore, we provide evidence supporting the notion that tumor growth promotion seen in IGF-I-treated parous rats is caused by activation of estrogen receptor-α via the Raf/Ras/mitogen-activated protein kinase cascade.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df75f599262bccdf0a0f25d9d0c12bf4
http://europepmc.org/articles/PMC468665 -
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المؤلفون: Tatsuya Toyama, Xueqing Wu, Hiroshi Sugiura, Hiroko Yamashita, Yoko Omoto, Hirotaka Iwase, Yasuo Hara, Zhenhuan Zhang, Shunzo Kobayashi
المصدر: Breast Cancer Research
مصطلحات موضوعية: Adult, medicine.medical_specialty, medicine.drug_class, Estrogen receptor, Breast Neoplasms, Biology, real-time RT-PCR, progesterone receptor, Disease-Free Survival, Gene Expression Regulation, Enzymologic, Breast cancer, breast cancer, Aromatase, Internal medicine, Progesterone receptor, medicine, Humans, RNA, Messenger, Estrogen receptor beta, Aged, Medicine(all), Aged, 80 and over, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Ductal, Breast, Age Factors, Estrogen Receptor alpha, Middle Aged, medicine.disease, Prognosis, Immunohistochemistry, aromatase mRNA, Reverse transcription polymerase chain reaction, Gene Expression Regulation, Neoplastic, Endocrinology, Receptors, Estrogen, Estrogen, Lymphatic Metastasis, biology.protein, Female, Receptors, Progesterone, Estrogen receptor alpha, Research Article, estrogen receptor
الوصف: Background Estrogen is a mitogenic factor that is implicated in the genesis and progression of breast cancer via its binding to estrogen receptor (ER)-α. Synthesis of estrogen in situ is believed to be catalyzed mainly by aromatase. Previous studies comparing the relative contributions from tumor cells and stromal cells to local estrogen synthesis, as assessed by immunohistochemical analysis, were quite controversial and no consistent relationship was found between the presence of aromatase and any clinicopathologic factor. In addition, previous studies into aromatase gene expression and clinicopathologic factors are limited. Methods We assessed the level of expression of aromatase mRNA, using quantitative real-time RT-PCR, in 162 cases of invasive ductal carcinoma of the breast. Associations between aromatase expression and different clinicopathologic factors were sought. Results It was found that aromatase mRNA was expressed at significantly higher levels in patients older than 50 years, in those without axillary lymph node involvement, in those with tumor size less than 2 cm, and in ER-α positive tumors. However, no relationship was found between aromatase mRNA expression and any other clinicopathologic factor, including histologic grade and progesterone receptor status. Patients with high levels of expression of aromatase mRNA tended to have a better prognosis than did those patients with low expression. Conclusion These findings imply that ER-α and aromatase may be coexpressed in endocrine responsive patients. They may also indicate that aromatase expression could be a marker of endocrine responsiveness, and it may have prognostic implications for breast cancer progression.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af53552260bc82256df7c959cac497b0
http://europepmc.org/articles/PMC314416 -
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المؤلفون: Zafar Nawaz, Xiuhua Gao
المصدر: Breast Cancer Research
مصطلحات موضوعية: Cell signaling, Transcription, Genetic, Breast Neoplasms, Review, Biology, progesterone receptor, Mice, breast cancer, Progesterone receptor, Animals, Humans, Nuclear Receptor Co-Repressor 1, Receptor, Transcription factor, Nuclear receptor co-repressor 1, Nuclear Proteins, corepressor, Receptor Cross-Talk, coactivator, Repressor Proteins, Disease Models, Animal, Nuclear receptor, Cancer research, Trans-Activators, Female, Signal transduction, Receptors, Progesterone, Corepressor, Cell Division, Signal Transduction
الوصف: Progesterone, an ovarian steroid hormone, plays a key role in the development and function of the mammary gland, as it also does in the uterus and the ovary. The action of progesterone is mediated through its intracellular cognate receptor, the progesterone receptor (PR), which functions as a transcription factor that regulates gene expression. As with other nuclear receptors, coregulators (coactivators and corepressors) recruited by the liganded or unliganded PR, either to enhance or to suppress transcription activity, modulate the function of the PR. Mutation or aberrant expression of the coregulators might thus affect the normal function of the PR and hence disrupt the normal development of the mammary gland, which may lead to breast cancer.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7f008519f13136ae87637989cfae2b91
http://europepmc.org/articles/PMC138741 -
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المؤلفون: Mohamed Bentires-Alj, Heike Brinkhaus, Fabienne Meier-Abt
المصدر: Breast Cancer Research : BCR
مصطلحات موضوعية: Cancer Research, medicine.medical_specialty, Letter, Mammary gland, Breast Neoplasms, Mice, Mammary Glands, Animal, Pregnancy, Internal medicine, WNT4, Progesterone receptor, medicine, Animals, Humans, Progenitor cell, skin and connective tissue diseases, Mammary Glands, Human, Wnt Signaling Pathway, Progesterone, Medicine(all), biology, Age Factors, Wnt signaling pathway, Epithelial Cells, medicine.disease, Parity, Endocrinology, medicine.anatomical_structure, Oncology, biology.protein, Versican, Female, Maternal Age, Hormone
الوصف: Early pregnancy has a strong and lifelong protective effect against breast cancer in humans and rodents [1-3]. This breast cancer protective effect is diminished or even reversed after late pregnancy [4]. As a potential mechanism for the early parity-induced protective effect, we and others have demonstrated that early parity induces differentiation of mammary epithelial cells [5-7]. Furthermore, early parity downregulates the Wnt/Notch signaling ratio and the in vitro and in vivo proliferation potential of basal stem/progenitor cells in mice [6,7]. These early parity-induced changes of gene expression and dynamics of mammary stem/progenitor cells were caused primarily by a decrease in the proportion of hormone-sensitive and Wnt4-secreting luminal epithelial cells [6,7]. Although the reported findings provided a valid explanation for the breast cancer protective effect of an early pregnancy, two important questions remained unanswered. First, the early parity-induced cellular and molecular changes in mammary epithelium were investigated at a single time point (tissue/cell harvest at 40 days after weaning), leaving the question of their persistence unanswered. Second, mice were always mated at the young age of 6 weeks, and hence the effects of late pregnancy were not addressed. To directly answer these open questions, we performed additional experiments in old mice (22 months old) that had completed an early pregnancy at 6 weeks and in mice that had gone through late pregnancy (mating at 24 weeks). As markers for the parity-induced decrease in mammary gland hormone responsiveness and the reduction of basal epithelial Wnt signaling [6], immunohistochemistry in mammary gland sections was performed for progesterone receptor (PR)-positive cells and for Wnt target gene expression (versican and keratin 15 [8]) as well as for epithelial cells expressing nuclear beta-catenin. Furthermore, Wnt4 expression was compared between mammary gland tissues of parous and age-matched virgin control mice. The results demonstrate that early pregnancy-induced reductions in the proportion of PR-positive cells and expression of basal epithelial Wnt targets versican and keratin 15 persist into advanced age, and thus are of lifelong duration in mice (Figure 1A). Furthermore, pregnancy occurring at a very late age had only marginal or even no effects on PR-positive cells and expression of Wnt targets versican and keratin 15 (Figure 1B). We also noticed changes in the proportion of PR-positive cells upon aging in nulliparous mice. However, because the data in the studies on 22-month-old mice with early pregnancy and 8-month-old mice with late pregnancy were derived from two independent experiments, no direct conclusions can be drawn for the effect of age per se on the proportion of PR-positive cells in nulliparous control mice. Figure 1 Effects of early and late parity on hormone (progesterone) sensitive cells and Wnt target gene (versican and keratin 15) expression in mice. (A) Early parity-induced decrease in expression of progesterone receptor (PR) and Wnt target genes versican and ... To further substantiate a persistent decrease of epithelial Wnt signaling by early parity, we extended the analysis to beta-catenin, a marker for active Wnt signaling. We found a persistent decrease in the proportion of nuclear beta-catenin-positive mammary epithelial cells from 11.1 ± 1.5% in 22-month-old age-matched virgins to 6.7 ± 0.9% in 22-month-old mice that had gone through pregnancy at an early age. In contrast, nuclear beta-catenin in epithelial cells was not affected by late pregnancy (10.8 ± 1.3% in age-matched virgins versus 9.6 ± 1.9% in parous mice) (data represent the mean ± standard deviation of 3,000 counted cells from six mice per group). Furthermore, we had previously shown that decreases in PR-positive cells were associated with decreases in Wnt4 expression, which in turn was associated with decreased Wnt signaling in basal stem/progenitor cells [6]. Consistent with the data for PR, the basal epithelial Wnt targets versican and keratin 15; and for nuclear beta-catenin in epithelial cells, Wnt4 expression was also persistently reduced after early pregnancy but remained unchanged after late pregnancy (Figure 1C). Together with the previously reported study [6], the findings presented here represent the first direct comparison of the effects of early and late pregnancy on hormone sensing cells and on epithelial Wnt signaling in the mammary gland. The data conform with the presence of parity-induced changes in the dynamics of mammary cell functions upon early pregnancy [9] and suggest their absence upon late pregnancy in mice [10,11]. Overall these results are fully consistent with the lifelong breast cancer protective effect of early but not late pregnancy in humans [7]. They reinforce the validity of the adopted mouse model to study prevention strategies against human breast cancer and highlight the need for further investigations into the molecular changes following late versus early pregnancy.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::12a264030c726f9c5e8a5bd3da480320
https://doi.org/10.1186/bcr3626 -
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المؤلفون: Wan Zhang, Peng Huang, Rui-Hua Xu, Jiale Dai, Naima Hammoudi, Helene Pelicano, Lajos Pusztai, Jinyun Liu
المصدر: Breast Cancer Research : BCR
مصطلحات موضوعية: Receptor, ErbB-2, Estrogen receptor, Triple Negative Breast Neoplasms, Mitochondrion, Biology, 03 medical and health sciences, Adenosine Triphosphate, Oxygen Consumption, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, medicine, Humans, Lactic Acid, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, 030304 developmental biology, Medicine(all), 0303 health sciences, TOR Serine-Threonine Kinases, medicine.disease, Glutathione, Hydrocarbons, Brominated, Mitochondria, 3. Good health, Glucose, Electron Transport Chain Complex Proteins, Receptors, Estrogen, Cell culture, 030220 oncology & carcinogenesis, Cancer cell, Immunology, Cancer research, Female, Propionates, Energy Metabolism, Reactive Oxygen Species, Receptors, Progesterone, Oxidation-Reduction, NADP, Signal Transduction, Research Article
الوصف: Introduction Triple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. TNBC is not amenable to endocrine therapy and often exhibit resistance to current chemotherapeutic agents, therefore, further understanding of the biological properties of these cancer cells and development of effective therapeutic approaches are urgently needed. Methods We first investigated the metabolic alterations in TNBC cells in comparison with other subtypes of breast cancer cells using molecular and metabolic analyses. We further demonstrated that targeting these alterations using specific inhibitors and siRNA approach could render TNBC cells more sensitive to cell death compared to other breast cancer subtypes. Results We found that TNBC cells compared to estrogen receptor (ER) positive cells possess special metabolic characteristics manifested by high glucose uptake, increased lactate production, and low mitochondrial respiration which is correlated with attenuation of mTOR pathway and decreased expression of p70S6K. Re-expression of p70S6K in TNBC cells reverses their glycolytic phenotype to an active oxidative phosphorylation (OXPHOS) state, while knockdown of p70S6K in ER positive cells leads to suppression of mitochondrial OXPHOS. Furthermore, lower OXPHOS activity in TNBC cells renders them highly dependent on glycolysis and the inhibition of glycolysis is highly effective in targeting TNBC cells despite their resistance to other anticancer agents. Conclusions Our study shows that TNBC cells have profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis. Due to their impaired mitochondrial function, TNBC cells are highly sensitive to glycolytic inhibition, suggesting that such metabolic intervention may be an effective therapeutic strategy for this subtype of breast cancer cells. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0434-6) contains supplementary material, which is available to authorized users.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::06cabc8e1eaee2ed6a32422f8c1b5fb3
https://doi.org/10.1186/s13058-014-0434-6
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