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Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.
Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment. In addition, BMPR2 mutant mice were crossed onto oestrogen receptor (ESR)1 and ESR2 knockout backgrounds to assess receptor specificity. Haemodynamic and metabolic outcomes were measured.Oestrogen inhibition both prevented and treated PAH in BMPR2 mutant mice. This was associated with reduction in metabolic defects including oxidised lipid formation, insulin resistance and rescue of peroxisome proliferator-activated receptor-γ and CD36. The effect was mediated primarily through ESR2, but partially through ESR1.Our data suggest that trials of oestrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects. Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause.
Copyright ©ERS 2017.
Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SOD(loxp/loxp) × Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.
Copyright © 2014 the American Physiological Society.
Tamoxifen (TMX) is a selective estrogen receptor modulator that is used as an estrogen receptor antagonist for the treatment and prevention of breast cancer. Whether TMX has antagonist activities in the human brain is less clear and its effects on cognitive function have not been experimentally explored. This study examined how TMX affected cognitive performance in older women using a model of anticholinergic drug-induced cognitive dysfunction. Twenty-one postmenopausal women were administered 20 mg of oral TMX or placebo for 3 months. Participants then took part in five drug challenges using the anticholinergic antinicotinic agent mecamylamine (MECA) and antimuscarinic agent scopolamine (SCOP) and were tested on a comprehensive battery including tasks of attention and psychomotor function, verbal episodic memory, and spatial navigation. After a 3-month placebo washout, participants were then crossed over to the alternate treatment and repeated the drug challenges after 3 months. Compared with placebo treatment, TMX significantly attenuated the impairment from cholinergic blockade on tasks of verbal episodic memory and spatial navigation, but effects on attentional/psychomotor tasks were more variable. Analysis by APOE genotype showed that APO ɛ4+ women showed a greater beneficial effect of TMX on reversing the cholinergic impairment than APO ɛ4- women on most tasks. This study provides evidence that TMX may act as an estrogen-like agonist to enhance cholinergic system activity and hippocampally mediated learning.
Neural stem cells (NSCs) persist in the subventricular zone (SVZ) of the adult brain. Location within this germinal region determines the type of neuronal progeny NSCs generate, but the mechanism of adult NSC positional specification remains unknown. We show that sonic hedgehog (Shh) signaling, resulting in high gli1 levels, occurs in the ventral SVZ and is associated with the genesis of specific neuronal progeny. Shh is selectively produced by a small group of ventral forebrain neurons. Ablation of Shh decreases production of ventrally derived neuron types, while ectopic activation of this pathway in dorsal NSCs respecifies their progeny to deep granule interneurons and calbindin-positive periglomerular cells. These results show that Shh is necessary and sufficient for the specification of adult ventral NSCs.
Copyright © 2011 Elsevier Inc. All rights reserved.
Estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer patients. Metastasis has been associated with chemokine signaling through the SDF-1-CXCR4 axis. Thus, the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be driven by SDF-1-CXCR4 signaling. Here we report that CXCR4 overexpression is indeed correlated with worse prognosis and decreased patient survival irrespective of the status of the estrogen receptor (ER). Constitutive activation of CXCR4 in poorly metastatic MCF-7 cells led to enhanced tumor growth and metastases that could be reversed by CXCR4 inhibition. CXCR4 overexpression in MCF-7 cells promoted estrogen independence in vivo, whereas exogenous SDF-1 treatment negated the inhibitory effects of treatment with the anti-estrogen ICI 182,780 on CXCR4-mediated tumor growth. The effects of CXCR4 overexpression were correlated with SDF-1-mediated activation of downstream signaling via ERK1/2 and p38 MAPK (mitogen activated protein kinase) and with an enhancement of ER-mediated gene expression. Together, these results show that enhanced CXCR4 signaling is sufficient to drive ER-positive breast cancers to a metastatic and endocrine therapy-resistant phenotype via increased MAPK signaling. Our findings highlight CXCR4 signaling as a rational therapeutic target for the treatment of ER-positive, estrogen-independent breast carcinomas needing improved clinical management.
© 2010 AACR.
Transcriptional cascades are required for the specification of serotonin (5-HT) neurons and behaviors modulated by 5-HT. Several cascade factors are expressed throughout the lifespan, which suggests that their control of behavior might not be temporally restricted to programming normal numbers of 5-HT neurons. We used new mouse conditional targeting approaches to investigate the ongoing requirements for Pet-1 (also called Fev), a cascade factor that is required for the initiation of 5-HT synthesis, but whose expression persists into adulthood. We found that Pet-1 was required after the generation of 5-HT neurons for multiple steps in 5-HT neuron maturation, including axonal innervation of the somatosensory cortex, expression of appropriate firing properties, and the expression of the Htr1a and Htr1b autoreceptors. Pet-1 was still required in adult 5-HT neurons to preserve normal anxiety-related behaviors through direct autoregulated control of serotonergic gene expression. These findings indicate that Pet-1 is required across the lifespan of the mouse and that behavioral pathogenesis can result from both developmental and adult-onset alterations in serotonergic transcription.
OBJECTIVE - Conditional gene targeting has been extensively used for in vivo analysis of gene function in β-cell biology. The objective of this study was to examine whether mouse transgenic Cre lines, used to mediate β-cell- or pancreas-specific recombination, also drive Cre expression in the brain.
RESEARCH DESIGN AND METHODS - Transgenic Cre lines driven by Ins1, Ins2, and Pdx1 promoters were bred to R26R reporter strains. Cre activity was assessed by β-galactosidase or yellow fluorescent protein expression in the pancreas and the brain. Endogenous Pdx1 gene expression was monitored using Pdx1(tm1Cvw) lacZ knock-in mice. Cre expression in β-cells and co-localization of Cre activity with orexin-expressing and leptin-responsive neurons within the brain was assessed by immunohistochemistry.
RESULTS - All transgenic Cre lines examined that used the Ins2 promoter to drive Cre expression showed widespread Cre activity in the brain, whereas Cre lines that used Pdx1 promoter fragments showed more restricted Cre activity primarily within the hypothalamus. Immunohistochemical analysis of the hypothalamus from Tg(Pdx1-cre)(89.1Dam) mice revealed Cre activity in neurons expressing orexin and in neurons activated by leptin. Tg(Ins1-Cre/ERT)(1Lphi) mice were the only line that lacked Cre activity in the brain.
CONCLUSIONS - Cre-mediated gene manipulation using transgenic lines that express Cre under the control of the Ins2 and Pdx1 promoters are likely to alter gene expression in nutrient-sensing neurons. Therefore, data arising from the use of these transgenic Cre lines must be interpreted carefully to assess whether the resultant phenotype is solely attributable to alterations in the islet β-cells.
PURPOSE - Although there is evidence for interaction between epidermal growth factor receptor (EGFR) and estrogen receptor (ER), it is still not clear how this affects response to endocrine therapies like tamoxifen. Here we assess the relationship between EGFR expression and tamoxifen response, with a new quantitative technology.
PATIENTS AND METHODS - A tissue microarray was constructed from breast cancer from a cohort of 564 patients enrolled in a randomized clinical trial for adjuvant tamoxifen treatment in early breast cancer, with a median follow-up of 14 years. EGFR expression was measured using automated quantitative analysis, a fluorescence-based method for quantitative analysis of in situ protein expression.
RESULTS - In ER-positive patients, tamoxifen-treated patients with low EGFR expression (n = 113) showed a significant effect by 2 years of adjuvant tamoxifen (P = .01), in contrast to no treatment effect in the EGFR-high group (n = 73, P = .69). The untreated group showed 49% v 57% 10-year recurrence-free survival for EGFR low versus high (P = .466) in the corresponding group of ER-positive patients. A significant beneficial effect of tamoxifen treatment was seen in the EGFR-low group (hazard ratio [HR] = 0.43 (95% CI, 0.22 to 0.84; P = .013) in contrast to no effect in the EGFR-high group (HR = 1.14; 95% CI, 0.59 to 2.22; P = .7) by using a Cox model.
CONCLUSION - This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.