Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 8; p. 167458
• Main Authors: Kato, Chikage, Iizuka-Ohashi, Mahiro, Honda, Mizuki, Konishi, Eiichi, Yokota, Isao, Boku, Shogen, Mizuta, Naruhiko, Morita, Midori, Sakaguchi, Koichi, Taguchi, Tetsuya, Watanabe, Motoki, Naoi, Yasuto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2024
• Subjects: Apoptosis - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic - drug effects; HER2-positive breast cancer; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Middle Aged; Prognosis; Rac1; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Statins; The mevalonate pathway; The mevalonate pathway; HER2-positive breast cancer; Rac1; Statins
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167458

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC. [Display omitted] •SREBF2 is upregulated with activated geranylgeranylation process of the mevalonate pathway in HER2-positive breast cancer.•Statins enhance the efficacy of HER2-targeting agents by inhibition of membrane localization of the geranylgeranylated Rac1.•Rac1 is a novel prognostic and predictive biomarker for the combination of HER2-targeting agents with statins.