The Experts below are selected from a list of 153 Experts worldwide ranked by ideXlab platform
Carlos L Arteaga - One of the best experts on this subject based on the ideXlab platform.
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hyperactivation of phosphatidylinositol 3 kinase promotes escape from Hormone Dependence in estrogen receptor positive human breast cancer
Journal of Clinical Investigation, 2010Co-Authors: Todd W Miller, Bryan T Hennessy, Ana M Gonzalezangulo, Gordon B Mills, Heidi Chen, Catherine F Higham, Carlos Garciaecheverria, Yu Shyr, Carlos L ArteagaAbstract:Many breast cancers exhibit a degree of Dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from Hormone Dependence in estrogen receptor–positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17β-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of Hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to Hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.
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hyperactivation of phosphatidylinositol 3 kinase promotes escape from Hormone Dependence in estrogen receptor positive human breast cancer
Journal of Clinical Investigation, 2010Co-Authors: Todd W Miller, Bryan T Hennessy, Ana M Gonzalezangulo, Gordon B Mills, Heidi Chen, Catherine F Higham, Carlos Garciaecheverria, Yu Shyr, Carlos L ArteagaAbstract:Many breast cancers exhibit a degree of Dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from Hormone Dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17beta-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of Hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to Hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.
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Hyperactivation of phosphatidylinositol-3 kinase promotes escape from Hormone Dependence in estrogen receptor–positive human breast cancer
Journal of Clinical Investigation, 2010Co-Authors: Todd W Miller, Bryan T Hennessy, Gordon B Mills, Heidi Chen, Catherine F Higham, Yu Shyr, Ana M. Gonzalez-angulo, Carlos Garcia-echeverria, Carlos L ArteagaAbstract:Many breast cancers exhibit a degree of Dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from Hormone Dependence in estrogen receptor–positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17β-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of Hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to Hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.
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cdk inhibitor p27kip1 and Hormone Dependence in breast cancer
Clinical Cancer Research, 2004Co-Authors: Carlos L ArteagaAbstract:p27 Kip1 is an important regulator of the G 1 to S transition. While a potent inhibitor of cyclin-dependent-kinase (Cdk)2, p27 is also involved in assembly of cyclin D/Cdk4 complexes. Although rarely mutated, p27 is functionally downregulated in many human cancers by mechanisms involving enhanced degradation, cytoplasmic mislocalization, and/or sequestration by cyclin D/Cdk complexes in response to oncogenic signals. Therefore, low levels and/or cytoplasmic localized p27 have been associated with enhanced malignancy and poor patient prognosis in many neoplasias including breast cancer. Recent data discussed below suggest that a threshold of p27 is required for response to antiestrogens and, conversely, that low levels predict for antiestrogen resistance. These results imply that Hormone receptor-positive tumors with low and/or cytosolic p27 respond poorly to antiestrogens and should be considered for alternative therapeutic strategies.
Sarah A Robertson - One of the best experts on this subject based on the ideXlab platform.
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diversity in phenotype and steroid Hormone Dependence in dendritic cells and macrophages in the mouse uterus
Biology of Reproduction, 2004Co-Authors: Sarah N Keenihan, Sarah A RobertsonAbstract:The dendritic cells and related antigen-presenting cells (APCs) that activate lymphocytes for acquired immunity in the female reproductive tract are not well characterized. The aim of the present study was to examine heterogeneity among uterine APCs in mice and, specifically, to determine whether phenotypically and functionally distinct subpopulations of dendritic cells and macrophages can be identified. Using immunohistochemistry, abundant cells expressing APC-restricted molecules major histocompatibility complex (MHC) class II, F4/80, class A scavenger receptor, macrosialin, and sialoadhesin were evident in estrous mice. Cells expressing the costimulatory molecule B7-2 were rarely observed. Flow cytometric analysis revealed three subpopulations of uterine APCs. Undifferentiated macrophages were F4/80-positive (1), MHC class II-negative (2) cells, of which 70‐80% expressed CD11b, but few expressed class A scavenger receptor, macrosialin, or sialoadhesin. Mature macrophages were F4/801/MHC class II1 cells, of which approximately 50% expressed CD11b, class A scavenger receptor, macrosialin, and sialoadhesin. Uterine dendritic cells were F4/ 802/MHC class II1 cells, with stimulatory immunoaccessory function relative to uterine macrophages and heterogeneous expression of dendritic markers 33D1, DEC205, CD11c, and CD1. Experiments in ovariectomized mice showed that undifferentiated macrophages were steroid Hormone dependent but that mature macrophages and dendritic cells persisted after depletion of ovarian steroid Hormones, although with altered phenotypes. In summary, our findings identify three discrete populations of APCs inhabiting the murine uterus and suggest that both mature macrophages and dendritic cells differentiate from undifferentiated macrophage precursor cells. Plasticity in the ontogenetic and functional relationships between uterine dendritic cells and macrophages likely is critical in regulating immune responses conducive to reproductive success. female reproductive tract, immunology, steroid Hormones, uterus
Edith C Kordon - One of the best experts on this subject based on the ideXlab platform.
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Origin and Progression of Pregnancy-Dependent Mammary Tumors Induced by New Mouse Mammary Tumor Virus Variants
Breast Cancer Research and Treatment, 2002Co-Authors: Valeria Buggiano, Carolina Schere Levy, Albana Gattelli, María Cecilia Cirio, Mariana Marfil, Irene Nepomnaschy, Isabel Piazzon, Luisa Helguero, Silvia Vanzulli, Edith C KordonAbstract:In order to study mechanisms of progression of mouse mammary tumor virus (MMTV)-induced pregnancy-dependent mammary lesions, we removed and serially transplanted 17 small tumors detected in MMTV-infected pregnant females. This gave rise to the same number of ' in vivo ' tumor lines. Hormone-dependency of the passages was determined by comparing tumor development in multiparous versus virgin hosts. We found that the first passages of most of these lesions (11/17) required pregnancy to grow. However, all these tumor lines lost their Hormone-Dependence through successive passages. The original pregnancy-dependent lesions were mostly multiclonal and showed high levels of estrogen and progesterone receptors. Alternatively, pregnancy-independent tumors arose as clonal dominant populations exhibiting a lower Hormone receptor content. Our data show that the progression of Hormone-dependent MMTV-induced mammary tumors is an irreversible process associated with the appearance of additional MMTV insertional events as well as alterations in the composition of the tumor cell population.
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Hormone Dependence of a mouse mammary tumor line induced in vivo by medroxyprogesterone acetate
Breast Cancer Research and Treatment, 1990Co-Authors: Edith C Kordon, Claudia Lanari, Roberto Meiss, Patricia Elizalde, Eduardo H Charreau, Christiane Dosne PasqualiniAbstract:The administration of MPA to virgin female BALB/c mice led to the development of mammary adenocarcinomas, which in furtherin vivo transplants gave rise to both MPA-dependent and MPA-independent lines. In this paper we chose one of the MPA-dependent lines with high contents of estrogen (ER) and progesterone (PR) receptors, and were able to demonstrate that a) the growth of these tumors could be manipulated by the administration or the withdrawal of the hormonal supply;b) PR were down-regulated in MPA-treated mice; c) progesterone had the same stimulatory effect as MPA on tumor growth; d) tumors did not grow in estrogen-treated mice; e) tumor growth was much lower in males than in females; f) the presence of the ovaries had a positive influence on tumor growth, even in the presence of MPA; g) the withdrawal of progestin pellets in ovariectomized mice usually led to complete remissions followed by regrowth of the tumors after several weeks; and h) the regrowing tumors maintained their steroid receptor pattern and (in 3 out of 4 cases) their Hormone-dependent behavior in further passages.
Abigail L Fowden - One of the best experts on this subject based on the ideXlab platform.
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development and thyroid Hormone Dependence of skeletal muscle mitochondrial function towards birth
The Journal of Physiology, 2020Co-Authors: Katie L Davies, Emily J Camm, E V Atkinson, T Lopez, A J Forhead, Andrew J Murray, Abigail L FowdenAbstract:KEY POINTS: Skeletal muscle energy requirements increase at birth but little is known about the development of mitochondria that provide most of the cellular energy as ATP. Thyroid Hormones are known regulators of adult metabolism and are important in driving several aspects of fetal development, including muscle fibre differentiation. Mitochondrial density and abundance of mitochondrial membrane proteins in skeletal muscle increased during late gestation. However, mitochondrial functional capacity, measured as oxygen consumption rate, increased primarily after birth. Fetal hypothyroidism resulted in significant reductions in mitochondrial function and density in skeletal muscle before birth. Mitochondrial function matures towards birth and is dependent on the presence of thyroid Hormones with potential implications for the health of pre-term and hypothyroid infants. ABSTRACT: Birth is a significant metabolic challenge with exposure to a pro-oxidant environment and the increased energy demands for neonatal survival. This study investigated the development of mitochondrial density and activity in ovine biceps femoris skeletal muscle during the perinatal period and examined the role of thyroid Hormones in these processes. Muscle capacity for oxidative phosphorylation increased primarily after birth but was accompanied by prepartum increases in mitochondrial density and the abundance of electron transfer system (ETS) complexes I-IV and ATP-synthase as well as by neonatal upregulation of uncoupling proteins. This temporal disparity between prepartum maturation and neonatal upregulation of mitochondrial oxidative capacity may protect against oxidative stress associated with birth while ensuring energy availability to the neonate. Fetal thyroid Hormone deficiency reduced oxidative phosphorylation and prevented the prepartum upregulation of mitochondrial density and ETS proteins in fetal skeletal muscle. Overall, the data show that mitochondrial function matures over the perinatal period and is dependent on thyroid Hormones, with potential consequences for neonatal viability and adult metabolic health.
Osamu Midorikawa - One of the best experts on this subject based on the ideXlab platform.
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combined histochemical and biochemical analysis of sex Hormone Dependence of ferric nitrilotriacetate induced renal lipid peroxidation in ddy mice
Cancer Research, 1990Co-Authors: Shinya Toyokuni, Shigeru Okada, Shuji Hamazaki, Yukiko Minamiyama, Yoshihiro Yamada, Ping Liang, Yasutomo Fukunaga, Osamu MidorikawaAbstract:Ferric nitrilotriacetate (Fe-NTA) induces renal proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rats and mice. Male animals are much more susceptible than female animals to both effects. Moreover, the distribution of the susceptible proximal tubules is different between male and female animals. The present study investigated the effects of castration and sex Hormones on Fe-NTA-induced renal lipid peroxidation. Male and female ddY mice were either left untreated, castrated, and/or treated with testosterone or estriol. Histochemical (reactivity to cold Schiff's reagent) and biochemical (thiobarbituric acid-reactive substance) evaluations were performed 1 h after the i.p. injection of Fe-NTA (5 mg iron/kg). Testosterone treatment and/or oophorectomy increased the Schiff positivity of the renal cortical proximal tubules and the amount of thiobarbituric acid-reactive substance (testosterone-treated female > intact female, P intact female, P intact female, P < 0.005). In contrast, estriol treatment and/or orchiectomy decreased the Schiff positivity of the renal cortical proximal tubules and the amount of thiobarbituric acid-reactive substance (estriol-treated male < intact male, P < 0.01; castrated male < intact male, P < 0.01; castrated and estriol-treated male < intact male, P < 0.005). Estradiol treatment produced similar results to estriol treatment (estradiol-treated male < intact male, P < 0.005). Castration and/or administration of the opposite sex Hormone reversed the sex difference in the distribution of proximal tubules susceptible to lipid peroxidation. However, the i.v. injection to male mice, 5 min prior to the Fe-NTA treatment, of conjugated estrogen that is promptly excreted via the urine produced no significant effect. Thus, altered metabolic pathways rather than the direct scavenging activity of estrogens seem to be involved in the sex Hormone-dependent difference of lipid peroxidation. Genetically determined sex Hormone status appears to have influenced the incidence of Fe-NTA-induced renal adenocarcinoma in intact animals.