{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:48:56Z","timestamp":1791323336724,"version":"4.3.1"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,5,2]],"date-time":"2013-05-02T00:00:00Z","timestamp":1367452800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2013,10]]},"abstract":"<jats:p>Acquisition of resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of estrogen receptor alpha (ER\u03b1)\u2010positive breast cancers. The Res\u2010Ana cells, a new model of acquired resistance to anastrozole, were established by long\u2010term exposure of aromatase\u2010overexpressing MCF\u20107 cells to this drug. These resistant cells developed ER\u2010independent mechanisms of resistance and decreased sensitivity to the AI letrozole or to ER\u03b1 antagonists. They also displayed a constitutive activation of the PI3K\/Akt\/mTOR pathway and a deregulated expression of several ErbB receptors. An observed increase in the phospho\u2010Akt\/Akt ratio between primary and matched recurrent breast tumors of patients who relapsed under anastrozole adjuvant therapy also argued for a pivotal role of the Akt pathway in acquired resistance to anastrozole. Ectopic overexpression of constitutively active Akt1 in control cells was sufficient to induce <jats:italic>de novo<\/jats:italic> resistance to anastrozole. Strikingly, combining anastrozole with the highly selective and allosteric Akt inhibitor MK\u20102206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings lead to us proposing a model of anastrozole\u2010acquired resistance based on the selection of cancer\u2010initiating\u2010like cells possessing self\u2010renewing properties, intrinsic resistance to anastrozole and sensitivity to MK\u20102206. Altogether, our work demonstrated that the Akt\/mTOR pathway plays a key role in resistance to anastrozole and that combining anastrozole with Akt\/mTOR pathway inhibitors represents a promising strategy in the clinical management of hormone\u2010dependent breast cancer patients.<\/jats:p>","DOI":"10.1002\/ijc.28182","type":"journal-article","created":{"date-parts":[[2013,3,30]],"date-time":"2013-03-30T08:07:23Z","timestamp":1364630843000},"page":"1589-1602","source":"Crossref","is-referenced-by-count":46,"title":["Molecular characterization of anastrozole resistance in breast cancer: Pivotal role of the Akt\/mTOR pathway in the emergence of <i>de novo<\/i> or acquired resistance and importance of combining the allosteric Akt inhibitor MK\u20102206 with an aromatase inhibitor"],"prefix":"10.1002","volume":"133","author":[{"given":"Paul","family":"Vilquin","sequence":"first","affiliation":[{"name":"ISPB Facult\u00e9 de Pharmacie, Universit\u00e9 Lyon 1 Lyon France"},{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Villedieu","sequence":"additional","affiliation":[{"name":"ISPB Facult\u00e9 de Pharmacie, Universit\u00e9 Lyon 1 Lyon France"},{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyne","family":"Grisard","sequence":"additional","affiliation":[{"name":"ISPB Facult\u00e9 de Pharmacie, Universit\u00e9 Lyon 1 Lyon France"},{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina Ben","family":"Larbi","sequence":"additional","affiliation":[{"name":"ISPB Facult\u00e9 de Pharmacie, Universit\u00e9 Lyon 1 Lyon France"},{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra E.","family":"Ghayad","sequence":"additional","affiliation":[{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre\u2010Etienne","family":"Heudel","sequence":"additional","affiliation":[{"name":"Centre L\u00e9on B\u00e9rard Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bachelot","sequence":"additional","affiliation":[{"name":"Centre L\u00e9on B\u00e9rard Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Corbo","sequence":"additional","affiliation":[{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Treilleux","sequence":"additional","affiliation":[{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"},{"name":"Centre L\u00e9on B\u00e9rard Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Vendrell","sequence":"additional","affiliation":[{"name":"ISPB Facult\u00e9 de Pharmacie, Universit\u00e9 Lyon 1 Lyon France"},{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale A.","family":"Cohen","sequence":"additional","affiliation":[{"name":"ISPB Facult\u00e9 de Pharmacie, Universit\u00e9 Lyon 1 Lyon France"},{"name":"INSERM U1052 CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon Lyon France"},{"name":"Centre L\u00e9on B\u00e9rard Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,5,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.3756"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4092"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0303"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4502"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.03.034"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-2073"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-2168"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6807"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5544"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-070909-182917"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00955.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24750"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:BREA.0000041623.21338.47"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.00857"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2010-0016"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.333"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.00778"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0857"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/35102167"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905718106"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djn123"},{"key":"e_1_2_7_23_1","first-page":"6949","article-title":"Stable expression of human aromatase complementary DNA in mammalian cells: a useful system for aromatase inhibitor screening","volume":"50","author":"Zhou DJ","year":"1990","journal-title":"Cancer Res"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-9-291"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2004.10.021"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210269"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1677\/JME-08-0076"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1061803"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2005.09.003"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2010.09.005"},{"key":"e_1_2_7_31_1","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K\u2010dependent feedback loop in human cancer","volume":"118","author":"Carracedo A","year":"2008","journal-title":"J Clin Invest"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200403069"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2925"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2003.11.007"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920111794295657"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0626"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdm170"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2611"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9776(08)70002-X"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0318"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-012-2105-6"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2402"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.18.8391"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.39.0708"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109653"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2544"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-1012"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1141"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907560106"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-012-2148-8"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.06.010"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fijc.28182","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.28182","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T12:18:52Z","timestamp":1696335532000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.28182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,2]]},"references-count":50,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,10]]}},"alternative-id":["10.1002\/ijc.28182"],"URL":"https:\/\/doi.org\/10.1002\/ijc.28182","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,5,2]]}}}