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Breast Cancer Research
Published in: Breast Cancer Research 5/2014

Open Access 01-10-2014 | Research article

Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase

Authors: Xiaoyong Fu, Chad J Creighton, Nrusingh C Biswal, Vijetha Kumar, Martin Shea, Sabrina Herrera, Alejandro Contreras, Carolina Gutierrez, Tao Wang, Sarmistha Nanda, Mario Giuliano, Gladys Morrison, Agostina Nardone, Kristen L Karlin, Thomas F Westbrook, Laura M Heiser, Pavana Anur, Paul Spellman, Sylvie M Guichard, Paul D Smith, Barry R Davies, Teresa Klinowska, Adrian V Lee, Gordon B Mills, Mothaffar F Rimawi, Susan G Hilsenbeck, Joe W Gray, Amit Joshi, C Kent Osborne, Rachel Schiff

Published in: Breast Cancer Research | Issue 5/2014

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Abstract

Introduction

Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.

Methods

Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.

Results

Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.

Conclusions

Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.
Appendix
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Literature
1.
Lopez-Knowles E, O'Toole SA, McNeil CM, Millar EK, Qiu MR, Crea P, Daly RJ, Musgrove EA, Sutherland RL: PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer. 2010, 126: 1121-1131.CrossRefPubMed
2.
Rimawi MF, Wiechmann LS, Wang YC, Huang C, Migliaccio I, Wu MF, Gutierrez C, Hilsenbeck SG, Arpino G, Massarweh S, Ward R, Soliz R, Osborne CK, Schiff R: Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clin Cancer Res. 2011, 17: 1351-1361. 10.1158/1078-0432.CCR-10-1905.CrossRefPubMed
3.
Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, Lluch A, Gray JW, Brown PH, Hilsenbeck SG, Osborne CK, Mills GB, Lee AV, Schiff R: Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER + breast cancer.Breast Cancer Res 2010, 12:R40.,
4.
Fu X, Osborne CK, Schiff R: Biology and therapeutic potential of PI3K signaling in ER+/HER2-negative breast cancer. Breast. 2013, 22: S12-S18. 10.1016/j.breast.2013.08.001.CrossRefPubMed
5.
Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt AN, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C: PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A. 2010, 107: 10208-10213. 10.1073/pnas.0907011107.CrossRefPubMedPubMedCentral
6.
Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT: An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008, 68: 6084-6091. 10.1158/0008-5472.CAN-07-6854.CrossRefPubMedPubMedCentral
7.
Shoman N, Klassen S, McFadden A, Bickis MG, Torlakovic E, Chibbar R: Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol. 2005, 18: 250-259. 10.1038/modpathol.3800296.CrossRefPubMed
8.
Tanic N, Milovanovic Z, Tanic N, Dzodic R, Juranic Z, Susnjar S, Plesinac-Karapandzic V, Tatic S, Dramicanin T, Davidovic R, Dimitrijevic B: The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients. Cancer Biol Ther. 2012, 13: 1165-1174. 10.4161/cbt.21346.CrossRefPubMedPubMedCentral
9.
Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, Lindsley CW, Arteaga CL: Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009, 69: 4192-4201. 10.1158/0008-5472.CAN-09-0042.CrossRefPubMedPubMedCentral
10.
Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A, Salmena L, Sampieri K, Haveman WJ, Brogi E, Richardson AL, Zhang J, Pandolfi PP: Subtle variations in Pten dose determine cancer susceptibility. Nat Genet. 2010, 42: 454-458. 10.1038/ng.556.CrossRefPubMedPubMedCentral
11.
Comprehensive molecular portraits of human breast tumours. Nature. 2012, 490: 61-70. 10.1038/nature11412.
12.
Meerbrey KL, Hu G, Kessler JD, Roarty K, Li MZ, Fang JE, Herschkowitz JI, Burrows AE, Ciccia A, Sun T, Schmitt EM, Bernardi RJ, Fu X, Bland CS, Cooper TA, Schiff R, Rosen JM, Westbrook TF, Elledge SJ: The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proc Natl Acad Sci U S A. 2011, 108: 3665-3670. 10.1073/pnas.1019736108.CrossRefPubMedPubMedCentral
13.
Biswal NC, Ayala-Orzoco C, Halas NJ, Joshi A: Calibrating the photo-thermal response of magneto-fluorescent gold nanoshells. Conf Proc IEEE Eng Med Biol Soc. 2011, 2011: 4776-4779.PubMed
14.
Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R: Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation.Breast Cancer Res 2011, 13:R121.,
15.
16.
Harvey JM, Clark GM, Osborne CK, Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999, 17: 1474-1481.PubMed
17.
Schroeder MP, Gonzalez-Perez A, Lopez-Bigas N: Visualizing multidimensional cancer genomics data.Genome Med 2013, 5:9.,
18.
Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, Rao M, Yu P, Dominguez-Vidana R, Liang AC, Solimini NL, Bernardi RJ, Yu B, Hsu T, Golding I, Luo J, Osborne CK, Creighton CJ, Hilsenbeck SG, Schiff R, Shaw CA, Elledge SJ, Westbrook TF: A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2012, 335: 348-353. 10.1126/science.1212728.CrossRefPubMed
19.
Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, Salzberg SL, Wold BJ, Pachter L: Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010, 28: 511-515. 10.1038/nbt.1621.CrossRefPubMedPubMedCentral
20.
Saldanha AJ: Java Treeview–extensible visualization of microarray data. Bioinformatics. 2004, 20: 3246-3248. 10.1093/bioinformatics/bth349.CrossRefPubMed
21.
Creighton CJ, Casa A, Lazard Z, Huang S, Tsimelzon A, Hilsenbeck SG, Osborne CK, Lee AV: Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol. 2008, 26: 4078-4085. 10.1200/JCO.2007.13.4429.CrossRefPubMedPubMedCentral
22.
Wardwell-Ozgo J, Dogruluk T, Gifford A, Zhang Y, Heffernan TP, van Doorn R, Creighton CJ, Chin L, Scott KL: HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome. Oncogene. 2014, 33: 1017-1026. 10.1038/onc.2013.30.CrossRefPubMed
23.
Laska EM, Meisner MJ: Testing whether an identified treatment is best. Biometrics. 1989, 45: 1139-1151. 10.2307/2531766.CrossRefPubMed
24.
Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, De Placido S, Osborne CK, Schiff R: Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst. 2007, 99: 694-705. 10.1093/jnci/djk151.CrossRefPubMed
25.
Massarweh S, Osborne CK, Jiang S, Wakeling AE, Rimawi M, Mohsin SK, Hilsenbeck S, Schiff R: Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res. 2006, 66: 8266-8273. 10.1158/0008-5472.CAN-05-4045.CrossRefPubMed
26.
Liu Y, Ludes-Meyers J, Zhang Y, Munoz-Medellin D, Kim HT, Lu C, Ge G, Schiff R, Hilsenbeck SG, Osborne CK, Brown PH: Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth. Oncogene. 2002, 21: 7680-7689. 10.1038/sj.onc.1205883.CrossRefPubMed
27.
Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM, Osborne CK: Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat. 1992, 24: 85-95. 10.1007/BF01961241.CrossRefPubMed
28.
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR: The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006, 313: 1929-1935. 10.1126/science.1132939.CrossRefPubMed
29.
Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR: mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 2004, 10: 594-601. 10.1038/nm1052.CrossRefPubMed
30.
Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D: Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res. 2006, 66: 3903-3911. 10.1158/0008-5472.CAN-05-4363.CrossRefPubMed
31.
Creighton CJ, Massarweh S, Huang S, Tsimelzon A, Hilsenbeck SG, Osborne CK, Shou J, Malorni L, Schiff R: Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts. Cancer Res. 2008, 68: 7493-7501. 10.1158/0008-5472.CAN-08-1404.CrossRefPubMedPubMedCentral
32.
Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L, Isola J, Bendahl PO, Rosen N, Hibshoosh H, Ringnér M, Borg A, Parsons R: Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007, 104: 7564-7569. 10.1073/pnas.0702507104.CrossRefPubMedPubMedCentral
33.
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008, 118: 3065-3074.PubMedPubMedCentral
34.
Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, Engelman JA: MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 2012, 72: 3228-3237. 10.1158/0008-5472.CAN-11-3747.CrossRefPubMedPubMedCentral
35.
Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N: mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 2011, 1: 248-259. 10.1158/2159-8290.CD-11-0085.CrossRefPubMedPubMedCentral
36.
Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chène P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, García-Echeverría C, Sellers WR, Voliva CF: Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012, 11: 317-328. 10.1158/1535-7163.MCT-11-0474.CrossRefPubMed
37.
Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, Ricketts SA, Cross D, Cosulich S, Chresta CC, Page K, Yates J, Lane C, Watson R, Luke R, Ogilvie D, Pass M: Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012, 11: 873-887. 10.1158/1535-7163.MCT-11-0824-T.CrossRefPubMed
38.
Guichard SM, Howard Z, Heathcote D, Roth M, Hughes G, Curwen J, Yates J, Logie A, Holt S, Chresta CM, Davies BR, Malagu K, Hummersone M, Pass SL, Green S, Pass M: AZD2014, a dual mTORC1 and mTORC2 inhibitor is differentiated from allosteric inhibitors of mTORC1 in ER+ breast cancer. In:103 rd Annual Meeting of the American Association for Cancer Research.Cancer Res 2012, 72:Abstract nr 917.,
39.
Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E: Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007, 13: 1576-1583. 10.1158/1078-0432.CCR-06-1150.CrossRefPubMed
40.
Lupien M, Meyer CA, Bailey ST, Eeckhoute J, Cook J, Westerling T, Zhang X, Carroll JS, Rhodes DR, Liu XS, Brown M: Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes Dev. 2010, 24: 2219-2227. 10.1101/gad.1944810.CrossRefPubMedPubMedCentral
41.
Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R: Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 2008, 68: 826-833. 10.1158/0008-5472.CAN-07-2707.CrossRefPubMed
42.
Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M: A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol. 2000, 14: 783-794. 10.1210/mend.14.6.0446.CrossRefPubMed
43.
O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006, 66: 1500-1508. 10.1158/0008-5472.CAN-05-2925.CrossRefPubMedPubMedCentral
44.
Leslie NR, Foti M: Non-genomic loss of PTEN function in cancer: not in my genes. Trends Pharmacol Sci. 2011, 32: 131-140. 10.1016/j.tips.2010.12.005.CrossRefPubMed
45.
Phuong NT, Kim SK, Lim SC, Kim HS, Kim TH, Lee KY, Ahn SG, Yoon JH, Kang KW: Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells. Breast Cancer Res Treat. 2011, 130: 73-83. 10.1007/s10549-010-1304-2.CrossRefPubMed
46.
Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I, Ou G, Wijekoon AC, Levental KR, Gilbert PM, Hwang ES, Chen YY, Weaver VM: Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nature Med. 2014, 20: 360-367. 10.1038/nm.3497.CrossRefPubMedPubMedCentral
47.
Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC: Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009, 16: 115-125. 10.1016/j.ccr.2009.06.006.CrossRefPubMedPubMedCentral
48.
49.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R: Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004, 96: 926-935. 10.1093/jnci/djh166.CrossRefPubMed
50.
Schalper KA, Li K, Rimm DL: PTEN mRNA positivity using in situ measurements is associated with better outcome in Tamoxifen treated breast cancer patients. In:35 th Annual CTRC-AACR San Antinio Breast Cancer Symposium.Cancer Res 2012, 72:Abstract P3-06-25.,
51.
Perez EA, Dueck AC, McCullough AE, Chen B, Geiger XJ, Jenkins RB, Lingle WL, Davidson NE, Martino S, Kaufman PA, Kutteh LA, Sledge GW, Harris LN, Gralow JR, Reinholz MM: Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J Clin Oncol. 2013, 31: 2115-2122. 10.1200/JCO.2012.42.2642.CrossRefPubMedPubMedCentral
52.
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012, 366: 520-529. 10.1056/NEJMoa1109653.CrossRefPubMed
53.
Carracedo A, Pandolfi PP: The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008, 27: 5527-5541. 10.1038/onc.2008.247.CrossRefPubMed
54.
Hernandez-Aya LF, Gonzalez-Angulo AM: Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist. 2011, 16: 404-414. 10.1634/theoncologist.2010-0402.CrossRefPubMedPubMedCentral
55.
Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, Januario T, Savage H, Punnoose E, Truong T, Zhou W, Berry L, Murray L, Amler L, Belvin M, Friedman LS, Lackner MR: In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009, 15: 4649-4664. 10.1158/1078-0432.CCR-09-0317.CrossRefPubMed
56.
Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL: Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation.Breast Cancer Res 2013, 15:R55.,
57.
Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, Lin L, Ellis MJ: Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer.Breast Cancer Res 2011, 13:R21.,
58.
Zhang X, Diaz MR, Yee D: Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells. Breast Cancer Res Treat. 2013, 139: 351-360. 10.1007/s10549-013-2541-y.CrossRefPubMedPubMedCentral
Metadata
Title
Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase
Authors
Xiaoyong Fu
Chad J Creighton
Nrusingh C Biswal
Vijetha Kumar
Martin Shea
Sabrina Herrera
Alejandro Contreras
Carolina Gutierrez
Tao Wang
Sarmistha Nanda
Mario Giuliano
Gladys Morrison
Agostina Nardone
Kristen L Karlin
Thomas F Westbrook
Laura M Heiser
Pavana Anur
Paul Spellman
Sylvie M Guichard
Paul D Smith
Barry R Davies
Teresa Klinowska
Adrian V Lee
Gordon B Mills
Mothaffar F Rimawi
Susan G Hilsenbeck
Joe W Gray
Amit Joshi
C Kent Osborne
Rachel Schiff
Publication date
01-10-2014
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2014
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-014-0430-x

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