RESUMEN
Among breast cancers, triple-negative breast cancer (TNBC) is the most poorly understood and is refractory to current targeted therapies. Using a genetic screen, we identify the PTPN12 tyrosine phosphatase as a tumor suppressor in TNBC. PTPN12 potently suppresses mammary epithelial cell proliferation and transformation. PTPN12 is frequently compromised in human TNBCs, and we identify an upstream tumor-suppressor network that posttranscriptionally controls PTPN12. PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR. The tumorigenic and metastatic potential of PTPN12-deficient TNBC cells is severely impaired upon restoration of PTPN12 function or combined inhibition of PTPN12-regulated tyrosine kinases, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting proto-oncogenic tyrosine kinases in TNBC and other cancers based on their profile of tyrosine-phosphatase activity.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 12/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 12/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Transformación Celular Neoplásica , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , MicroARNs/metabolismo , Mutación , Metástasis de la Neoplasia , Procesamiento Proteico-PostraduccionalRESUMEN
We investigated transfer of artificial grammar learning in adults with and without dyslexia in 3 experiments. In Experiment 1, participants implicitly learned an artificial grammar system and were tested on new items that included the same symbols. In Experiment 2, participants were given practice with letter strings and then tested on strings created with a different letter set. In Experiment 3, participants were given practice with shapes and then tested on strings created with different shapes. Results show that in Experiment 1, both groups demonstrated utilization of pre-trained instances in the subsequent grammaticality judgement task, while in Experiments 2 (orthographic) and 3 (nonorthographic), only typically developed participants demonstrated application of knowledge from training to test. A post hoc analysis comparing between the experiments suggests that being trained and tested on an orthographic task leads to better performance than a nonorthographic task among typically developed adults but not among adults with dyslexia. Taken together, it appears that following extensive training, individuals with dyslexia are able to form stable representations from sequential stimuli and use them in a subsequent task that utilizes strings of similar symbols. However, the manipulation of the symbols challenges this ability.
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Dislexia , Aprendizaje , Humanos , Adulto , Lingüística , Juicio , ConocimientoRESUMEN
While G protein-coupled receptors (GPCRs) are known to be excellent drug targets, the second largest family of adhesion-GPCRs is less explored for their role in health and disease. ADGRF1 (GPR110) is an adhesion-GPCR and has an important function in neurodevelopment and cancer. Despite serving as a poor predictor of survival, ADGRF1's coupling to G proteins and downstream pathways remain unknown in cancer. We evaluated the effects of ADGRF1 overexpression on tumorigenesis and signaling pathways using two human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC) cell-line models. We also interrogated publicly available clinical datasets to determine the expression of ADGRF1 in various BC subtypes and its impact on BC-specific survival (BCSS) and overall survival (OS) in patients. ADGRF1 overexpression in HER2+ BC cells increased secondary mammosphere formation, soft agar colony formation, and % of Aldefluor-positive tumorigenic population in vitro and promoted tumor growth in vivo. ADGRF1 co-immunoprecipitated with both Gαs and Gαq proteins and increased cAMP and IP1 when overexpressed. However, inhibition of only the Gαs pathway by SQ22536 reversed the pro-tumorigenic effects of ADGRF1 overexpression. RNA-sequencing and RPPA analysis revealed inhibition of cell cycle pathways with ADGRF1 overexpression, suggesting cellular quiescence, as also evidenced by cell cycle arrest at the G0/1 phase and resistance to chemotherapy in HER2+ BC. ADGRF1 was significantly overexpressed in the HER2-enriched BC compared to luminal A and B subtypes and predicted worse BCSS and OS in these patients. Therefore, ADGRF1 represents a novel drug target in HER2+ BC, warranting discovery of novel ADGRF1 antagonists.
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Resistencia a Antineoplásicos/genética , Proteínas Oncogénicas/genética , Receptor ErbB-2/genética , Receptores Acoplados a Proteínas G/genética , Animales , Neoplasias de la Mama/genética , Carcinogénesis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Fase G1/genética , Humanos , Ratones , Ratones Desnudos , Fase de Descanso del Ciclo Celular/genética , Transducción de Señal/genéticaRESUMEN
Steroid hormones are pivotal modulators of pathophysiological processes in many organs, where they interact with nuclear receptors to regulate gene transcription. However, our understanding of hormone action at the single cell level remains incomplete. Here, we focused on estrogen stimulation of the well-characterized GREB1 and MYC target genes that revealed large differences in cell-by-cell responses, and, more interestingly, between alleles within the same cell, both over time and hormone concentration. We specifically analyzed the role of receptor level and activity state during allele-by-allele regulation and found that neither receptor level nor activation status are the determinant of maximal hormonal response, indicating that additional pathways are potentially in place to modulate cell- and allele-specific responses. Interestingly, we found that a small molecule inhibitor of the arginine methyltransferases CARM1 and PRMT6 was able to increase, in a gene specific manner, the number of active alleles/cell before and after hormonal stimulation, suggesting that mechanisms do indeed exist to modulate hormone receptor responses at the single cell and allele level.
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Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción Genética , Estrógenos/metabolismo , Hormonas Esteroides Gonadales/genética , Histona Acetiltransferasas/genética , Humanos , Conformación Molecular , Proteínas Nucleares/antagonistas & inhibidores , Unión Proteica/genética , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Análisis de la Célula IndividualRESUMEN
SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2-MSX2-SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.
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Resistencia a Antineoplásicos , Proteínas F-Box/metabolismo , Proteínas F-Box/fisiología , Proteínas de Homeodominio/metabolismo , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Factores de Transcripción SOXB1/metabolismo , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis , Proliferación Celular , Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas F-Box/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Pronóstico , Pirimidinas/farmacología , Factores de Transcripción SOXB1/genética , Tasa de Supervivencia , Tamoxifeno/farmacología , Células Tumorales Cultivadas , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+ breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2- metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α-dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
RESUMEN
Previous studies have shown that distributed practice-a training strategy that is known to facilitate memory-is likely to result in greater learning than massed practice. This effect has been demonstrated largely in explicit tasks. The purpose of this study was to test whether statistical learning of artificial grammar is affected by the lag between learning sessions overall, and by high and low complexity stimuli (as measure by chunk strength). Two groups (spaced-short and spaced-long) learned strings of letters created according to a set of rules and were required to produce new strings using given letter sets. For the spaced-short group, the two learning sessions, each including training and a test phase, took place sequentially with a 10-min break, whereas for the spaced-long group, learning sessions were distributed across two days (1-day lag). Overall results showed improved performance following spaced-long practice compared to spaced-short practice. The results also indicated that in the low chunk strength strings (indicating high complexity), both groups demonstrated similar improvement from first to second testing, while in the high chunk strength strings (indicating low complexity), improvement in letter reordering performance was significantly higher when the learning sessions were distributed across two days. This pattern of findings suggests that stimuli complexity affects the extent to which distributed practice enhance artificial grammar learning.
Asunto(s)
Aprendizaje , Lingüística , Humanos , MemoriaRESUMEN
Estrogen receptor (ER) is the major driver of most metastatic breast cancers (mBCs). Endocrine therapy (ET) is the most effective treatment for ER + mBC, but its effectiveness is limited by high rates of de novo and acquired resistance. A growing understanding of the biological characteristics and complexity of the ER pathway and the mechanisms of ET resistance has led to the development of a new generation of targeted therapies. One such mechanism is the cell cycle signaling pathways, which lead to the development of cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) that have, in turn, transformed the management of such tumors. Another important mechanism is the alteration of the phosphatidylinositol 3'-kinase/AKT/mammalian target of rapamycin pathway. Drugs targeting each component of these pathways are currently used in clinical practice, and several more are in development. As a result, a myriad of new targeted therapies are consistently being added to the clinical oncologist armamentarium. Navigating the evolving and highly complex treatment landscape of HR + /HER2- mBC remains both an art and a challenge. In this review, we discuss the biological features of HR + /HER2- mBC and the different mechanisms of resistance to ET. We also discuss the management of mBC as the disease changes from endocrine-sensitive to endocrine-resistant.
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Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Factor de Crecimiento Epidérmico , Femenino , Humanos , Fosfatidilinositol 3-Quinasa , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genética , Transducción de SeñalRESUMEN
BACKGROUND: Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. METHODS: The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. RESULTS: Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. CONCLUSION: ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/genética , Proteínas Portadoras/genética , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/genética , Proteínas de Fusión Oncogénica , Receptor ErbB-2/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Dasatinib/administración & dosificación , Femenino , Fulvestrant/administración & dosificación , Humanos , Lapatinib/administración & dosificación , Ratones , Ratones Desnudos , Receptor ErbB-2/antagonistas & inhibidores , Transducción de Señal , Tamoxifeno/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
An accumulating body of evidence highlights the contribution of general cognitive processes, such as attention, to language-related skills. OBJECTIVE: The purpose of the present study was to explore how interference control (a subcomponent of selective attention) is affected in developmental dyslexia (DD) by means of control over simple stimulus-response mappings. Furthermore, we aimed to examine interference control in adults with DD across sensory modalities. METHODS: The performance of 14 dyslexic adults and 14 matched controls was compared on visual/auditory Simon tasks, in which conflict was presented in terms of an incongruent mapping between the location of a visual/auditory stimulus and the appropriate motor response. RESULTS: In the auditory task, dyslexic participants exhibited larger Simon effect costs; namely, they showed disproportionately larger reaction times (RTs)/errors costs when the auditory stimulus and response were incongruent relative to RT/errors costs of non-impaired readers. In the visual Simon task, both groups presented Simon effect costs to the same extent. CONCLUSION: These results indicate that the ability to control auditory selective attention is carried out less effectively in those with DD compared with visually controlled processing. The implications of this impaired process for the language-related skills of individuals with DD are discussed.
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Atención/fisiología , Percepción Auditiva/fisiología , Dislexia/fisiopatología , Función Ejecutiva/fisiología , Inhibición Psicológica , Percepción Visual/fisiología , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
HER2-positive breast cancers are defined by amplification of the cerbB2 gene and overexpression of its protein HER2. This subtype of breast cancer is aggressive, grows rapidly, and metastasizes early. However, new treatments targeting HER2 combined with chemotherapy have dramatically altered the course of patients harboring this type of breast cancer. Traditionally, these patients have been treated with aggressive combination chemotherapy, combined with trastuzumab, an antibody that blocks HER2 signaling and also induces antibody-dependent cellular cytotoxicity. Trastuzumab combined with newer drugs that also block HER2 signaling has been shown to be effective even in the absence of chemotherapy. Significant pathologic complete response (pCR) rates have been observed with dual targeted therapy in preclinical studies and in neoadjuvant trials in patients without chemotherapy. Before this de-escalation strategy can become part of routine clinical care, biomarkers need to be developed that identify patients who either do or do not respond well to such therapies.
RESUMEN
The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.
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Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Factor de Transcripción SOX9/metabolismo , Antineoplásicos Hormonales/farmacología , Mama/química , Mama/metabolismo , Neoplasias de la Mama/química , Neoplasias de la Mama/fisiopatología , Proliferación Celular/efectos de los fármacos , Cromatina/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Humanos , Células MCF-7 , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/farmacología , Tamoxifeno/farmacologíaRESUMEN
BACKGROUND: The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations. METHODS: Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models. RESULTS: In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance. CONCLUSIONS: These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models.
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Neoplasias de la Mama/tratamiento farmacológico , Cinamatos/administración & dosificación , Indoles/administración & dosificación , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Receptores de Estrógenos/antagonistas & inhibidores , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Estradiol/genética , Estradiol/metabolismo , Estrógenos/genética , Estrógenos/metabolismo , Femenino , Fulvestrant/administración & dosificación , Xenoinjertos , Humanos , Células MCF-7 , Ratones , Neoplasias Hormono-Dependientes/genética , Receptores de Estrógenos/genética , Tamoxifeno/administración & dosificaciónRESUMEN
BACKGROUND: Breast cancer patient-derived xenograft (BC-PDX) models represent a continuous and reproducible source of circulating tumor cells (CTCs) for studying their role in tumor biology and metastasis. We have previously shown the utility of BC-PDX models in the study of CTCs by immunohistochemistry (IHC) on serial paraffin sections and manual microscopic identification of cytokeratin-positive cells, a method that is both low-throughput and labor-intensive. We therefore aimed to identify and characterize CTCs from small volume mouse blood samples and examined its practical workflow in a study of BC-PDX mice treated with chemotherapy using an automated imaging platform, the AccuCyte®-CyteFinder® system. METHODS: CTC analysis was conducted using blood from non-tumor bearing SCID/Beige mice spiked with human breast cancer cells, BC-PDX-bearing mice, and BC-PDX mice treated with vehicle or chemotherapeutic agent(s). After red blood cell lysis, nucleated cells were mixed with transfer solution, processed onto microscope slides, and stained by immunofluorescence. The CyteFinder automated scanning microscope was used to identify CTCs, defined as nucleated cells that were human cytokeratin-positive, and mouse CD45-negative. Disaggregated primary BC-PDX tumors and lung metastatic nodules were processed using the same immunostaining protocol. Collective expression of breast cancer cell surface markers (EpCAM, EGFR, and HER2) using a cocktail of target-specific antibodies was assessed. CTCs and disaggregated tumor cells were individually retrieved from slides using the CytePicker® module for sequence analysis of a BC-PDX tumor-specific PIK3CA mutation. RESULTS: The recovery rate of human cancer cells spiked into murine blood was 83 ± 12%. CTC detection was not significantly different from the IHC method. One-third of CTCs did not stain positive for cell surface markers. A PIK3CA T1035A mutation present in a BC-PDX tumor was confirmed in isolated single CTCs and cells from dissociated metastatic nodules after whole genome amplification and sequencing. CTC evaluation could be simply implemented into a preclinical PDX therapeutic study setting with substantial improvements in workflow over the IHC method. CONCLUSIONS: Analysis of small volume blood samples from BC-PDX-bearing mice using the AccuCyte-CyteFinder system allows investigation of the role of CTCs in tumor biology and metastasis independent of surface marker expression.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Células Neoplásicas Circulantes/metabolismo , Análisis de la Célula Individual/métodos , Animales , Antineoplásicos/farmacología , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Separación Celular , Fosfatidilinositol 3-Quinasa Clase I/sangre , Femenino , Humanos , Queratinas/sangre , Antígenos Comunes de Leucocito/sangre , Ratones , Ratones SCID , Mutación , Trasplante de Neoplasias , Células Neoplásicas Circulantes/efectos de los fármacos , Análisis de Secuencia de ADNRESUMEN
Recently, it has been suggested that developmental dyslexia (DD) is related to deficits in general mechanisms of statistical learning (SL). The aim of the current study was to explore these relations using a nonlinguistic auditory artificial grammar learning (A-AGL) task. Most studies using AGL to explore the role of SL among readers with dyslexia used visual stimuli. The current study explored SL abilities among adults with DD using a nonlinguistic auditory task, because evidence suggests that SL is affected by the modality of stimuli. Forty-eight (21 DD and 27 typically developed [TD]) adults participated in two A-AGL tasks: implicit and explicit. The results showed a significant difference between the groups, as TD readers outperformed adults with DD. This difference in performance supports the SL deficit hypothesis among adults with dyslexia, although the causal relations between auditory SL and reading still require further examination. In addition, no difference was found between the implicit and explicit tasks, suggesting that unlike the visual AGL, participants with DD do not benefit from elevating attentional resources during A-AGL.
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Percepción Auditiva , Dislexia/psicología , Aprendizaje , Adulto , Femenino , Humanos , Lingüística , Masculino , Lectura , Adulto JovenRESUMEN
Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.
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Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Interleucina-8/genética , Transcriptoma , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Interleucina-8/antagonistas & inhibidores , Interleucina-8/metabolismo , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Análisis de Supervivencia , Tamoxifeno/uso terapéuticoRESUMEN
More than 40% of patients with luminal breast cancer treated with endocrine therapy agent tamoxifen demonstrate resistance. Emerging evidence suggests tumor initiating cells (TICs) and aberrant activation of Src and Akt signaling drive tamoxifen resistance and relapse. We previously demonstrated that aryl hydrocarbon receptor ligand aminoflavone (AF) inhibits the expression of TIC gene α6-integrin and disrupts mammospheres derived from tamoxifen-sensitive breast cancer cells. In the current study, we hypothesize that tamoxifen-resistant (TamR) cells exhibit higher levels of α6-integrin than tamoxifen-sensitive cells and that AF inhibits the growth of TamR cells by suppressing α6-integrin-Src-Akt signaling. In support of our hypothesis, TamR cells and associated mammospheres were found to exhibit elevated α6-integrin expression compared with their tamoxifen-sensitive counterparts. Furthermore, tumor sections from patients who relapsed on tamoxifen showed enhanced α6-integrin expression. Gene expression profiling from the TCGA database further revealed that basal-like breast cancer samples, known to be largely unresponsive to tamoxifen, demonstrated higher α6-integrin levels than luminal breast cancer samples. Importantly, AF reduced TamR cell viability and disrupted TamR mammospheres while concomitantly reducing α6-integrin messenger RNA and protein levels. In addition, AF and small interfering RNA against α6-integrin blocked tamoxifen-stimulated proliferation of TamR MCF-7 cells and further sensitized these cells to tamoxifen. Moreover, AF reduced Src and Akt signaling activation in TamR MCF-7 cells. Our findings suggest elevated α6-integrin expression is associated with tamoxifen resistance and AF suppresses α6-integrin-Src-Akt signaling activation to confer activity against TamR breast cancer.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Flavonoides/farmacología , Integrina alfa6/genética , Receptores de Hidrocarburo de Aril/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ligandos , Células MCF-7 , Células Madre Neoplásicas/efectos de los fármacos , Proteína Oncogénica v-akt/genética , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Transducción de Señal , Tamoxifeno/efectos adversos , Familia-src Quinasas/genéticaRESUMEN
PURPOSE: G protein-coupled receptors (GPCRs) represent the largest family of druggable targets in human genome. Although several GPCRs can cross-talk with the human epidermal growth factor receptors (HERs), the expression and function of most GPCRs remain unknown in HER2+ breast cancer (BC). In this study, we aimed to evaluate gene expression of GPCRs in tumorigenic or anti-HER2 drug-resistant cells and to understand the potential role of candidate GPCRs in HER2+ BC. METHODS: Gene expression of 352 GPCRs was profiled in Aldeflur+ tumorigenic versus Aldeflur- population and anti-HER2 therapy-resistant derivatives versus parental cells of HER2+ BT474 cells. The GPCR candidates were confirmed in 7 additional HER2+ BC cell line models and publicly available patient dataset. Anchorage-dependent and anchorage-independent cell growth, mammosphere formation, and migration/invasion were evaluated upon GPR110 knockdown by siRNA in BT474 and SKBR3 parental and lapatinib+ trastuzumab-resistant (LTR) cells. RESULTS: Adhesion and class A GPCRs were overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population of BT474 cells, respectively. GPR110 was the only GPCR overexpressed in Aldeflur+ and anti-HER2 therapy-resistant population in BT474, SKBR3, HCC1569, MDA-MB-361, AU565, and/or HCC202 cells and in HER2+ BC subtype in patient tumors. Using BT474 and SKBR3 parental and LTR cells, we found that GPR110 knockdown significantly reduced anchorage-dependent/independent cell growth as well as migration/invasion of parental and LTR cells and mammosphere formation in LTR derivatives and not in parental cells. CONCLUSION: Our data suggest a potential role of GPR110 in tumorigenicity and in tumor cell dissemination in HER2+ BC.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas Oncogénicas/metabolismo , Receptor ErbB-2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Terapia Molecular Dirigida , Proteínas Oncogénicas/genética , ARN Interferente Pequeño/genética , Receptor ErbB-2/genética , Receptores Acoplados a Proteínas G/genética , Reproducibilidad de los Resultados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy. PATIENTS AND METHODS: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). RESULTS: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). CONCLUSION: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfohidrolasa PTEN/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lapatinib , Persona de Mediana Edad , Mutación , Terapia Neoadyuvante/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Receptor ErbB-2/genética , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversosRESUMEN
HER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1-4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.