title: Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin.
abstract: A review of the literature finds that women diagnosed with breast cancer, who were on an aspirin regimen, experienced a decreased risk of distant metastases and death. Several recent studies have reported an improvement in overall survival in colorectal cancer patients who harbored mutations in the oncogene PIK3CA and received a daily aspirin regimen. Breast cancer patients on a daily aspirin regimen experienced decreased risk of distant metastases and death. PIK3CA is the most frequently mutated oncogene in breast cancer, occurring in up to 45 % of all breast cancers. In order to determine if mutations in PIK3CA sensitized breast cancers to aspirin treatment, we employed the use of isogenic cellular clones of the non-tumorigenic, breast epithelial cell line MCF-10A that harbored mutations in either PIK3CA or KRAS or both. We report that mutations in both PIK3CA and KRAS are required for the greatest aspirin sensitivity in breast cancer, and that the GSK3β protein was hyperphosphorylated in aspirin-treated double knockin cells, but not in other clones/treatments. A more modest effect was observed with single mutant PIK3CA, but not KRAS alone. These observations were further confirmed in a panel of breast cancer cell lines. Our findings provide the first evidence that mutations in PIK3CA sensitize breast cancer cells to aspirin.
authors.affiliation: Department of Internal Medicine, Division of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 60612, USA.
authors.forename: Sanja B
authors.initials: SB
authors.lastname: Turturro
authors.affiliation: Department of Internal Medicine, Division of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 60612, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Najor
authors.affiliation: Department of Surgery, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 60612, USA.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Ruby
authors.affiliation: Department of Internal Medicine, Division of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 60612, USA.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Cobleigh
authors.affiliation: Department of Internal Medicine, Division of Hematology, Oncology, and Cell Therapy, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 60612, USA. abde_abukhdeir@rush.edu.|Department of Pharmacology, Rush University Medical Center, 1735 W. Harrison St., Chicago, IL, 60612, USA. abde_abukhdeir@rush.edu.
authors.forename: Abde M
authors.identifier: http://orcid.org/0000-0003-1172-5819
authors.initials: AM
authors.lastname: Abukhdeir
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D054697:Cytostatic Agents / Q000494:pharmacology*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: D054697:Cytostatic Agents; C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D016283:Proto-Oncogene Proteins p21(ras); D001241:Aspirin
keywords: Aspirin; Breast cancer; Drug resistance; Genetics; KRAS; PIK3CA