Abstract
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 (GABAA 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.
Highlights
Breast cancer is a heterogeneous disease comprised of different molecular subtypes, which can be identified through gene or biomarker expression analyses and are predictive of prognosis[1,2,3]
Using Oil red O staining to analyze neutral fat contents, we observed a higher intensity of Oil red O in the cells treated with diptoindonesin G (Dip G), which is similar to the result with the cell differentiation inducer NaB (Fig. 1d)
Dip G downregulated the expression of the basal-like genes CD44 and cytokeratin (CK) 5, accompanied by upregulation of the luminallike genes FOXA1 and GATA-binding protein 3 (GATA3) expression in a timedependent manner (Fig. 1e)
Summary
Breast cancer is a heterogeneous disease comprised of different molecular subtypes, which can be identified through gene or biomarker expression analyses and are predictive of prognosis[1,2,3]. Luminal-like breast cancer, which includes luminal A and B subtypes, is characterized by the expression of estrogen receptor (ER) and/or progesterone (PR) and confers a more favorable prognosis partially due to anti-hormone therapy responsiveness[4]. Recent studies have proposed luminal progenitors as the common origin of both luminal and basal-like breast cancers[7,8,9]. A tumorigenic subpopulation of luminal progenitors could dedifferentiate to acquire a basal-like phenotype. Basal-like cancer cells show a high degree of heterogeneity and plasticity[10,11,12,13]. A recent study demonstrated that intervention of platelet-derived growth factor
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