Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1

• Published in: Cell death & disease Vol. 11; no. 8; p. 635
• Main Authors: Fan, Minmin, Chen, Jingwei, Gao, Jian, Xue, Wenwen, Wang, Yixuan, Li, Wuhao, Zhou, Lin, Li, Xin, Jiang, Chengfei, Sun, Yang, Wu, Xuefeng, Wu, Xudong, Ge, Huiming, Shen, Yan, Xu, Qiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.08.2020; Springer Nature B.V
• Subjects: 14/63; 38/39; 38/77; 38/89; 38/91; 631/154/436/434; 631/67/1347; 64; 64/60; 82; 82/29; 96; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Animal models; Animals; Antibodies; Benzofurans - metabolism; Benzofurans - pharmacology; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Culture; Cell Differentiation - drug effects; Cell Line, Tumor; China; Estrogen Receptor beta - drug effects; Estrogen Receptor beta - metabolism; Female; GABARAP protein; Gene expression; Gene Expression - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunology; Life Sciences; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins - metabolism; Microtubule-Associated Proteins - physiology; Natural products; Neoplasm Recurrence, Local - genetics; Neoplasms, Basal Cell - metabolism; Phenotypes; Prognosis; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Tamoxifen; Tamoxifen - pharmacology; Transcriptomes; Tumor cell lines; Tumors; γ-Aminobutyric acid A receptors; China
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02878-z

Breast cancer is a heterogeneous disease that includes different molecular subtypes. The basal-like subtype has a poor prognosis and a high recurrence rate, whereas the luminal-like subtype confers a more favorable patient prognosis partially due to anti-hormone therapy responsiveness. Here, we demonstrate that diptoindonesin G (Dip G), a natural product, exhibits robust differentiation-inducing activity in basal-like breast cancer cell lines and animal models. Specifically, Dip G treatment caused a partial transcriptome shift from basal to luminal gene expression signatures and prompted sensitization of basal-like breast tumors to tamoxifen therapy. Dip G upregulated the expression of both GABARAPL1 (GABA A receptor-associated protein-like 1) and ERβ. We revealed a previously unappreciated role of GABARAPL1 as a regulator in the specification of breast cancer subtypes that is dependent on ERβ levels. Our findings shed light on new therapeutic opportunities for basal-like breast cancer via a phenotype switch and indicate that Dip G may serve as a leading compound for the therapy of basal-like breast cancer.