title: Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling.
abstract: Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiologic studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA Here, we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on COX-2 and NF-κB. We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mTORC1 inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, whereas combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports the evaluation of aspirin and PI3K pathway inhibitors as a combination therapy for targeting breast cancer. Cancer Res; 77(3); 790-801. ©2016 AACR.
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Whitney S
authors.initials: WS
authors.lastname: Henry
authors.affiliation: Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Tyler
authors.initials: T
authors.lastname: Laszewski
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tsang
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Harvard Stem Cell Institute, Cambridge, Massachusetts.
authors.forename: Francisco
authors.initials: F
authors.lastname: Beca
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Harvard Stem Cell Institute, Cambridge, Massachusetts.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Harvard Stem Cell Institute, Cambridge, Massachusetts.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McAllister
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts. atoker@bidmc.harvard.edu.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D055372:AMP-Activated Protein Kinases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D058534:Class I Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C484760:PIK3CA protein, human