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Autophagy has tumor\u2010promoting and \u2010suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER+ breast cancer cells. PI3K inhibition with GDC\u20100941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor\u2010induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3\u2010only proapoptotic proteins Bim and PUMA. Treatment with GDC\u20100941, CQ, or the combination, significantly suppressed the growth of ER+ breast cancer xenografts in mice. In an antiestrogen\u2010resistant xenograft model, GDC\u20100941 syn\u2010 ergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER+ breast cancer.\u2014Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phos\u2010 phatidylinositol 3\u2010kinase inhibition in estrogen receptor\u2010positive breast cancer. FASEB J. 32, 1222\u20101235 (2018).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700477r","type":"journal-article","created":{"date-parts":[[2017,11,10]],"date-time":"2017-11-10T12:10:26Z","timestamp":1510315826000},"page":"1222-1235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Autophagy promotes escape from phosphatidylinositol 3\u2010kinase inhibition in estrogen receptor\u2010positive breast cancer"],"prefix":"10.1096","volume":"32","author":[{"given":"Wei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Molecular and Systems Biology Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah R.","family":"Hosford","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole A.","family":"Traphagen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Shee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene","family":"Demidenko","sequence":"additional","affiliation":[{"name":"Community and Family Medicine Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd W.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"},{"name":"Comprehensive Breast Program Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth Lebanon New Hampshire USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,1,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60993-8"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumours","volume":"490","author":"Cancer Genome Atlas, N.; Cancer Genome Atlas Network","year":"2012","journal-title":"Nature"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr3039"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1158\/1078-0432.CCR-15-2276","article-title":"Strategically timing inhibition of phosphatidylinositol 3\u2010kinase to maximize therapeutic index in estrogen receptor \u03b1\u2010positive, PIK3CA\u2010mutant breast cancer","volume":"22","author":"Yang W.","year":"2016","journal-title":"Clin. 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