Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer
Background: Tamoxifen remains a cornerstone of adjuvant therapy for hormone receptor-positive breast cancer. Despite its proven efficacy, challenges such as limited drug sensitivity and endocrine resistance continue to pose significant clinical hurdles. This study aimed to investigate fatostatin, a compound shown to sensitize breast cancer to the antitumor effects of tamoxifen, both in vitro and in vivo.
Methods: Fatostatin-induced estrogen receptor (ER) degradation was assessed through immunoprecipitation. The combined antitumor effect of fatostatin and tamoxifen on MCF-7 and T47D cells was evaluated using MTT and colony formation assays. Cell cycle arrest was analyzed by flow cytometry, while apoptosis was measured through annexin V/propidium iodide staining and TUNEL assays. Autophagy was examined using MDC and acridine orange staining. Migration and invasion were evaluated through Transwell assays, and the in vivo efficacy of fatostatin and tamoxifen combination therapy was tested using an MCF-7 xenograft model in BALB/c nu/nu female mice.
Results: The combination of fatostatin and tamoxifen significantly reduced cell viability and invasion, induced cell cycle arrest, and modulated apoptosis and autophagy in MCF-7 and T47D cell lines via the PI3K-AKT-mTOR pathway. Following treatment with fatostatin and tamoxifen, there was an increase in the expression of Atg7/12/13, beclin, and LC3B, while levels of p-mTOR and P62 were reduced. In the xenograft model, tumor growth was notably suppressed with the synergistic treatment.
Conclusion: Fatostatin induces ER degradation through K48-linked polyubiquitination, a key mechanism contributing to tamoxifen’s inhibition of PI3K-AKT-mTOR signaling in breast cancer. These findings suggest that fatostatin could have promising clinical applications for patients with ER-positive breast cancer.