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Cancer Res. 2017 Feb 1;77(3):790-801. doi: 10.1158/0008-5472.CAN-16-2400. Epub 2016 Dec 9.

Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling.

Henry WS1,2, Laszewski T3, Tsang T1,2, Beca F1,2,4,5, Beck AH1,2,4,5, McAllister SS2,3,4,5, Toker A6,2.

Author information

1
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
2
Harvard Medical School, Boston, Massachusetts.
3
Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts.
4
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
5
Harvard Stem Cell Institute, Cambridge, Massachusetts.
6
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts. atoker@bidmc.harvard.edu.

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.

PMID:
27940576
PMCID:
PMC5290090
DOI:
10.1158/0008-5472.CAN-16-2400
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors disclose no potential conflict of interest

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