Novel Therapeutic Combination Targets the Growth of Letrozole-Resistant Breast Cancer through Decreased Cyclin B1.

Abstract

As breast cancer cells transition from letrozole-sensitive to letrozole-resistant, they over-express epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and human epidermal growth factor receptor 2 (HER2) while acquiring enhanced motility and epithelial-to-mesenchymal transition (EMT)-like characteristics that are attenuated and reversed by glyceollin treatment, respectively. Interestingly, glyceollin inhibits the proliferation and tumor progression of triple-negative breast cancer (TNBC) and estrogen-independent breast cancer cells; however, it is unlikely that a single phytochemical would effectively target aromatase-inhibitor (AI)-resistant metastatic breast cancer in the clinical setting. Since our previous report indicated that the combination of lapatinib and glyceollin induced apoptosis in hormone-dependent AI-resistant breast cancer cells, we hypothesized that combination therapy would also be beneficial for hormone independent letrozole-resistant breast cancer cells (LTLT-Ca) compared to AI-sensitive breast cancer cells (AC-1) by decreasing the expression of proteins associated with proliferation and cell cycle progression. While glyceollin + lapatinib treatment caused comparable inhibitory effects on the proliferation and migration in both cell lines, combination treatment selectively induced S and G2/M phase cell cycle arrest of the LTLT-Ca cells, which was mediated by decreased cyclin B1. This phenomenon may represent a unique opportunity to design novel combinatorial therapeutic approaches to target hormone-refractory breast tumors.

• Authors: Jankiben R Patel, Bipika Banjara, Afia Ohemeng, A Michael Davidson, Stephen M Boué, Matthew E Burow, Syreeta L Tilghman
• Journal: Nutrients (Nutrients) Vol. 15 Issue 7 (Mar 28 2023) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 37049472 (Publication Type: Journal Article)

Chemical References

• Letrozole
• Lapatinib
• Cyclin B1
• Nitriles
• Triazoles
• Aromatase Inhibitors
• Estrogens
• Mitogen-Activated Protein Kinases

Topics

• Humans
• Female
• Letrozole (pharmacology)
• Breast Neoplasms (metabolism)
• Lapatinib (pharmacology)
• Cyclin B1 (pharmacology)
• Nitriles (pharmacology)
• Triazoles (pharmacology)
• Drug Resistance, Neoplasm
• Aromatase Inhibitors (pharmacology, therapeutic use)
• Estrogens (metabolism)
• Mitogen-Activated Protein Kinases
• Cell Line, Tumor