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Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer

Department of Biochemistry & Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
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Author to whom correspondence should be addressed.
Academic Editor: Zhixiang Wang
Cancers 2021, 13(12), 2922; https://doi.org/10.3390/cancers13122922
Received: 10 May 2021 / Revised: 9 June 2021 / Accepted: 10 June 2021 / Published: 11 June 2021
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
About one third of all breast cancers are classified as HER2-positive due to high levels of the HER2 cell surface protein. Drugs that target HER2 have been mostly successful, but this type of cancer returns at a high frequency once treatment has been completed. The high levels of HER2 also cause elevated activation of mechanistic target of rapamycin (mTOR) and enhanced glucose metabolism, both of which support cancer growth. Based on this, drugs have been developed to block mTOR and tested in clinical studies alone or in combination with drugs that target HER2. These treatments are successful but have more toxic effects and a higher chance that the cancer will return. Using drugs that mimic glucose deprivation in HER2-positive breast cancer patients has not been tested; however, preclinical studies have shown HER2-positive breast tumors are reduced by combining drugs that mimic glucose deprivation with mTOR inhibitors.
Up to one third of all breast cancers are classified as the aggressive HER2-positive subtype, which is associated with a higher risk of recurrence compared to HER2-negative breast cancers. The HER2 hyperactivity associated with this subtype drives tumor growth by up-regulation of mechanistic target of rapamycin (mTOR) pathway activity and a metabolic shift to glycolysis. Although inhibitors targeting the HER2 receptor have been successful in treating HER2-positive breast cancer, anti-HER2 therapy is associated with a high risk of recurrence and drug resistance due to stimulation of the PI3K-Akt-mTOR signaling pathway and glycolysis. Combination therapies against HER2 with inhibition of mTOR improve clinical outcomes compared to HER2 inhibition alone. Here, we review the role of the HER2 receptor, mTOR pathway, and glycolysis in HER2-positive breast cancer, along with signaling mechanisms and the efficacy of treatment strategies of HER2-positive breast cancer. View Full-Text
Keywords: mTOR; glycolysis; HER2-positive breast cancer; 2-deoxyglucose; trastuzumab; Herceptin; LKB1; tumor recurrence; rapalog; PI3K-Akt-mTOR signaling pathway; clinical diagnostics mTOR; glycolysis; HER2-positive breast cancer; 2-deoxyglucose; trastuzumab; Herceptin; LKB1; tumor recurrence; rapalog; PI3K-Akt-mTOR signaling pathway; clinical diagnostics
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MDPI and ACS Style

Holloway, R.W.; Marignani, P.A. Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer. Cancers 2021, 13, 2922. https://doi.org/10.3390/cancers13122922

AMA Style

Holloway RW, Marignani PA. Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer. Cancers. 2021; 13(12):2922. https://doi.org/10.3390/cancers13122922

Chicago/Turabian Style

Holloway, Ryan W., and Paola A. Marignani. 2021. "Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer" Cancers 13, no. 12: 2922. https://doi.org/10.3390/cancers13122922

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