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Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, Sudhan DR, Guerrero-Zotano AL, Croessmann S, Guo Y, Ericsson PG, Lee KM, Nixon MJ, Schwarz LJ, Sanders ME, Dugger TC, Cruz MR, Behdad A, Cristofanilli M, Bardia A, O'Shaughnessy J, Nagy RJ, Lanman RB, Solovieff N, He W, Miller M, Su F, Shyr Y, Mayer IA, Balko JM, Arteaga CL
(2019) Nat Commun 10: 1373
MeSH Terms: Aminopyridines, Animals, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Circulating Tumor DNA, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Female, Fulvestrant, High-Throughput Nucleotide Sequencing, Humans, MCF-7 Cells, Mice, Mutation, Naphthalenes, Piperazines, Progression-Free Survival, Proportional Hazards Models, Protein Kinase Inhibitors, Purines, Pyrazoles, Pyridines, Quinolines, Quinoxalines, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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32 MeSH Terms
Genomic profiling of ER breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.
Giltnane JM, Hutchinson KE, Stricker TP, Formisano L, Young CD, Estrada MV, Nixon MJ, Du L, Sanchez V, Ericsson PG, Kuba MG, Sanders ME, Mu XJ, Van Allen EM, Wagle N, Mayer IA, Abramson V, Gόmez H, Rizzo M, Toy W, Chandarlapaty S, Mayer EL, Christiansen J, Murphy D, Fitzgerald K, Wang K, Ross JS, Miller VA, Stephens PJ, Yelensky R, Garraway L, Shyr Y, Meszoely I, Balko JM, Arteaga CL
(2017) Sci Transl Med 9:
MeSH Terms: Breast Neoplasms, Cell Line, Tumor, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Female, Humans, In Vitro Techniques, Receptor, ErbB-2, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Estrogen
Show Abstract · Added March 14, 2018
Inhibition of proliferation in estrogen receptor-positive (ER) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER/human epidermal growth factor receptor 2-negative (HER2) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including and , respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER/ coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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11 MeSH Terms
Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells.
Banerjee RR, Cyphert HA, Walker EM, Chakravarthy H, Peiris H, Gu X, Liu Y, Conrad E, Goodrich L, Stein RW, Kim SK
(2016) Diabetes 65: 2331-41
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Cyclin A2, Cyclin B1, Cyclin B2, Cyclin D1, Cyclin D2, Diabetes, Gestational, Female, Forkhead Box Protein M1, Insulin, Insulin-Secreting Cells, MafB Transcription Factor, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pregnancy, Receptors, Prolactin, Serotonin, Signal Transduction, Tryptophan Hydroxylase
Show Abstract · Added September 19, 2016
β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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23 MeSH Terms
Comprehensive genomic profiles of small cell lung cancer.
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK
(2015) Nature 524: 47-53
MeSH Terms: Alleles, Animals, Cell Line, Tumor, Chromosome Breakpoints, Cyclin D1, DNA-Binding Proteins, Disease Models, Animal, Female, Gene Expression Profiling, Genome, Human, Genomics, Humans, Lung Neoplasms, Male, Mice, Mutation, Neurosecretory Systems, Nuclear Proteins, Receptors, Notch, Retinoblastoma Protein, Signal Transduction, Small Cell Lung Carcinoma, Tumor Protein p73, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Show Abstract · Added February 16, 2016
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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25 MeSH Terms
Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice.
Scheving LA, Zhang X, Stevenson MC, Threadgill DW, Russell WE
(2015) Am J Physiol Gastrointest Liver Physiol 308: G364-77
MeSH Terms: Animals, Carbon Tetrachloride, Chemical and Drug Induced Liver Injury, Cyclin A, Cyclin D1, Epidermal Growth Factor, ErbB Receptors, Hepatocytes, Liver Regeneration, Mice, Neuregulin-1, Proto-Oncogene Proteins c-met, Receptor, ErbB-3
Show Abstract · Added May 5, 2016
The role(s) of the epidermal growth factor receptor (EGFR) in hepatocytes is unknown. We generated a murine hepatocyte specific-EGFR knockout (KO) model to evaluate how loss of hepatocellular EGFR expression affects processes such as EGF clearance, circulating EGF concentrations, and liver regeneration following 70% resection or CCl4-induced centrilobular injury. We were able to disrupt EGFR expression effectively in hepatocytes and showed that the ability of EGF and heregulin (HRG) to phosphorylate EGFR and ERBB3, respectively, required EGFR. Loss of hepatocellular EGFR impaired clearance of exogenous EGF from the portal circulation but paradoxically resulted in reduced circulating levels of endogenous EGF. This was associated with decreased submandibular salivary gland production of EGF. EGFR disruption did not result in increased expression of other ERBB proteins or Met, except in neonatal mice. Liver regeneration following 70% hepatectomy revealed a mild phenotype, with no change in cyclin D1 expression and slight differences in cyclin A expression compared with controls. Peak 5-bromo-2'-deoxyuridine labeling was shifted from 36 to 48 h. Centrilobular damage and regenerative response induced by carbon tetrachloride (CCl4) were identical in the KO and wild-type mice. In contrast, loss of Met increased CCl4-induced necrosis and delayed regeneration. Although loss of hepatocellular EGFR alone did not have an effect in this model, EGFR-Met double KOs displayed enhanced necrosis and delayed liver regeneration compared with Met KOs alone. This suggests that EGFR and Met may partially compensate for the loss of the other, although other compensatory mechanisms can be envisioned.
Copyright © 2015 the American Physiological Society.
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13 MeSH Terms
Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma.
Andl T, Le Bras GF, Richards NF, Allison GL, Loomans HA, Washington MK, Revetta F, Lee RK, Taylor C, Moses HL, Andl CD
(2014) Carcinogenesis 35: 2602-10
MeSH Terms: Animals, Antigens, CD, Cadherins, Carcinogenesis, Carcinoma, Squamous Cell, Cell Proliferation, Cyclin D1, Epithelial Cells, Homeostasis, Humans, Mice, Mouth Neoplasms, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Tamoxifen
Show Abstract · Added December 3, 2014
Although the etiology of squamous cell carcinomas of the oral mucosa is well understood, the cellular origin and the exact molecular mechanisms leading to their formation are not. Previously, we observed the coordinated loss of E-cadherin (CDH1) and transforming growth factor beta receptor II (TGFBR2) in esophageal squamous tumors. To investigate if the coordinated loss of Cdh1 and Tgfbr2 is sufficient to induce tumorigenesis in vivo, we developed two mouse models targeting ablation of both genes constitutively or inducibly in the oral-esophageal epithelium. We show that the loss of both Cdh1 and Tgfbr2 in both models is sufficient to induce squamous cell carcinomas with animals succumbing to the invasive disease by 18 months of age. Advanced tumors have the ability to invade regional lymph nodes and to establish distant pulmonary metastasis. The mouse tumors showed molecular characteristics of human tumors such as overexpression of Cyclin D1. We addressed the question whether TGFβ signaling may target known stem cell markers and thereby influence tumorigenesis. From our mouse and human models, we conclude that TGFβ signaling regulates key aspects of stemness and quiescence in vitro and in vivo. This provides a new explanation for the importance of TGFβ in mucosal homeostasis.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
2 Communities
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17 MeSH Terms
Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.
Zheng X, Zhai B, Koivunen P, Shin SJ, Lu G, Liu J, Geisen C, Chakraborty AA, Moslehi JJ, Smalley DM, Wei X, Chen X, Chen Z, Beres JM, Zhang J, Tsao JL, Brenner MC, Zhang Y, Fan C, DePinho RA, Paik J, Gygi SP, Kaelin WG, Zhang Q
(2014) Genes Dev 28: 1429-44
MeSH Terms: Animals, Cell Line, Cells, Cultured, Cyclin D1, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Regulation, Neoplastic, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, MCF-7 Cells, Mice, Protein Binding, Protein Stability, Ubiquitin Thiolesterase
Show Abstract · Added March 4, 2015
The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.
© 2014 Zheng et al.; Published by Cold Spring Harbor Laboratory Press.
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14 MeSH Terms
Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice.
Zeng F, Miyazawa T, Kloepfer LA, Harris RC
(2014) Kidney Int 86: 538-47
MeSH Terms: Animals, Apoptosis, Blood Urea Nitrogen, Caspase 3, Cell Proliferation, Cyclin D, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, Disease Progression, Epithelial Cells, Fibrosis, Gene Deletion, Kidney Cortex, Kidney Medulla, Mice, Organ Size, Polycystic Kidney Diseases, Receptor, ErbB-4
Show Abstract · Added October 27, 2014
ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.
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19 MeSH Terms
Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.
Nagathihalli NS, Beesetty Y, Lee W, Washington MK, Chen X, Lockhart AC, Merchant NB
(2014) Cancer Res 74: 2062-72
MeSH Terms: ADAM Proteins, ADAM17 Protein, Amphiregulin, Bile Acids and Salts, Cyclin D1, Deoxycholic Acid, EGF Family of Proteins, ErbB Receptors, Gastrointestinal Neoplasms, Glycoproteins, HCT116 Cells, Humans, Intercellular Signaling Peptides and Proteins, Pancreas, Phosphorylation, Receptors, G-Protein-Coupled, STAT3 Transcription Factor, Transforming Growth Factor alpha, src-Family Kinases
Show Abstract · Added February 14, 2014
Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both colorectal cancer and PDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment.
©2014 AACR.
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19 MeSH Terms
Mapping C-terminal transactivation domains of the nuclear HER family receptor tyrosine kinase HER3.
Brand TM, Iida M, Luthar N, Wleklinski MJ, Starr MM, Wheeler DL
(2013) PLoS One 8: e71518
MeSH Terms: Cell Line, Cell Nucleus, Cyclin D1, Humans, Mutation, Promoter Regions, Genetic, Protein Structure, Tertiary, Receptor, ErbB-3, Transcriptional Activation
Show Abstract · Added June 22, 2015
Nuclear localized HER family receptor tyrosine kinases (RTKs) have been observed in primary tumor specimens and cancer cell lines for nearly two decades. Inside the nucleus, HER family members (EGFR, HER2, and HER3) have been shown to function as co-transcriptional activators for various cancer-promoting genes. However, the regions of each receptor that confer transcriptional potential remain poorly defined. The current study aimed to map the putative transactivation domains (TADs) of the HER3 receptor. To accomplish this goal, various intracellular regions of HER3 were fused to the DNA binding domain of the yeast transcription factor Gal4 (Gal4DBD) and tested for their ability to transactivate Gal4 UAS-luciferase. Results from these analyses demonstrated that the C-terminal domain of HER3 (CTD, amino acids distal to the tyrosine kinase domain) contained potent transactivation potential. Next, nine HER3-CTD truncation mutants were constructed to map minimal regions of transactivation potential using the Gal4 UAS-luciferase based system. These analyses identified a bipartite region of 34 (B₁) and 27 (B₂) amino acids in length that conferred the majority of HER3's transactivation potential. Next, we identified full-length nuclear HER3 association and regulation of a 122 bp region of the cyclin D1 promoter. To understand how the B₁ and B₂ regions influenced the transcriptional functions of nuclear HER3, we performed cyclin D1 promoter-luciferase assays in which HER3 deleted of the B₁ and B₂ regions was severely hindered in regulating this promoter. Further, the overexpression of HER3 enhanced cyclin D1 mRNA expression, while HER3 deleted of its identified TADs was hindered at doing so. Thus, the ability for HER3 to function as a transcriptional co-activator may be dependent on specific C-terminal TADs.
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9 MeSH Terms