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

  • Biochim Biophys Acta Mol Basis Dis. 2024 Aug 10;1870(8):167458. doi: 10.1016/j.bbadis.2024.167458.
Chikage Kato  1 ,  Mahiro Iizuka-Ohashi  1 ,  Mizuki Honda  2 ,  Eiichi Konishi  2 ,  Isao Yokota  3 ,  Shogen Boku  4 ,  Naruhiko Mizuta  5 ,  Midori Morita  1 ,  Koichi Sakaguchi  1 ,  Tetsuya Taguchi  1 ,  Motoki Watanabe  6 ,  Yasuto Naoi  1
Affiliations
  • 1. Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • 2. Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • 3. Department of Biostatistics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • 4. Cancer Treatment Center, Kansai Medical University Hospital, Osaka, Japan.
  • 5. Mizuta Breast Clinic, Kyoto, Japan.
  • 6. Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: [email protected].
PMID: 39128642 DOI: 10.1016/j.bbadis.2024.167458
Abstract

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.

Keywords
HER2-positive breast cancer; Rac1; Statins; The mevalonate pathway.
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