Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer

Abstract

The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer (TNBC). Herein, we demonstrated that changes in the expression of Yes-associated protein (YAP) and β-catenin might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity in TNBC patients. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against drug-resistant TNBC cells as well as the sensitivity of these cells to the agents in vitro and in vivo. Interestingly, aspirin not only significantly inhibited the growth of TNBC cells, but also attenuated YAP and β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP to abolished docetaxel and vinorelbine resistance. The combination of aspirin and docetaxel or vinorelbine remarkably inhibited the growth of drug-resistant TNBC cells in vitro and in vivo. Moreover, TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression. Collectively, our study discovered a novel role of aspirin based on its anticancer effect, and put forward some possible mechanisms of chemoresistance in TNBC. The combined use of aspirin and anti-microtubule drugs presented several promising therapeutic approaches for TNBC treatment.

Targeting XPO6 inhibits prostate cancer progression and enhances the suppressive efficacy of docetaxel

“…Accumulating evidence not only suggests oncogenic roles of Hippo pathway in cancer progression, but also its roles in chemotherapy resistance. For example, YAP1 could mediate DTX resistance in triple-negative breast cancer and its decreased expression could enhance the cytotoxicity of DTX and reverse drug resistance [ 24 ]. Similarly, YAP1 mediates DTX resistance in PCa [ 25 – 27 ].…”

LncRNA AGAP2-AS1 Promotes Cancer Cell Proliferation, Migration and Invasion in Colon Cancer by Forming a Negative Feedback Loop with LINC-PINT

“…Yes-associated protein (YAP), a downstream regulator of the Hippo pathway, is upregulated in cancers and is involved in proliferation, apoptosis, migration, invasion. 18 The decreased phosphorylation level of LATS1, YAP was found after the overexpression of AGAP2-AS1, while LINC-PINT has the opposite effect. Furthermore, overexpression of AGAP2-AS1 improved the YAP translocation, while LINC-PINT decreased the nuclear level of YAP.…”

Chemoprophylaxis of precancerous lesions in patients who are at a high risk of developing colorectal cancer (Review)

“…The risk was 20% lower after 5 years of use and 30% lower after 10 years of use, while increasing the dosage up to 100 mg/day decreased the risk by 10%, and up to 325 mg/day, by 35% ( 73 ). Aspirin also locally reduces the expression of β-catenin ( 74 ).…”