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PP-81

EK100 inhibits breast cancer osteolytic bone metastasis by suppressing the

mevalonate pathway

#,1
Haritha Rengamanar, Chih-Hsin Tang* ,2,3,4

1 Graduate Institute of Biological Science and Technology, China Medical University, Taichung,
Taiwan.
2 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
3 Department of Pharmacology, School of Medicine, China Medical University, Taichung,
Taiwan.
4 Chinese Medicine Research Center, China Medical University, Taichung, Taiwan 40402.
* E-mail: chtang@mail.cmu.edu.tw

Abstract
Bone metastasis is a major complication of breast cancer, affecting more than 70% of patients
and leading to severe morbidity through osteolytic lesions. Current therapeutic options provide
limited survival benefit and are often associated with significant side effects, highlighting the
need for safer alternatives. EK100 (ergostatrien-3β-ol), a natural compound derived from
Antrodia camphorata, has documented anticancer activity; however, its role in breast cancer–
associated bone metastasis has not been fully elucidated. In this study, we demonstrate that
EK100 inhibits breast cancer cell migration and invasion. Transcriptomic profiling revealed
that metabolic pathways were highly affected by EK100 treatment, with a significant
suppression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting
enzyme in cholesterol biosynthesis via the mevalonate pathway. Overexpression of HMGCR
enhanced breast cancer cell migration, invasion, and cholesterol synthesis, whereas EK100
treatment abrogated these effects. Furthermore, breast cancer cells that disseminate to bone
promote osteoclast differentiation and activation, leading to osteolytic bone metastasis.
Interestingly, EK100 significantly reduced osteoclast formation induced by breast cancer cell–
conditioned medium and suppressed osteolytic bone metastasis in vivo. Overall, EK100
disrupts HMGCR-mediated activation of the mevalonate pathway and osteoclastogenesis,
thereby attenuating breast cancer–induced osteolytic bone metastasis. Owing to its natural
origin and favorable safety profile, EK100 represents a promising therapeutic candidate for the
treatment of breast cancer bone metastasis.

Keywords: EK100; HMGCR; Osteolytic bone metastasis