Glyceollins Trigger Anti-Proliferative Effects in Hormone-Dependent Aromatase-Inhibitor-Resistant Breast Cancer Cells through the Induction of Apoptosis

• Published in: International journal of molecular sciences 2022-03, Vol.23 (5), p.2887
• Main Authors: Walker, Rashidra R, Patel, Jankiben R, Gupta, Akash, Davidson, A Michael, Williams, Christopher C, Payton-Stewart, Florastina, Boué, Stephen M, Burow, Matthew E, Khupse, Rahul, Tilghman, Syreeta L
• Format: Article
• Language: English
• Subjects: Apoptosis; Aromatase; Aromatase Inhibitors - pharmacology; Aromatase Inhibitors - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Drug Resistance, Neoplasm; ErbB-2 protein; Estrogen receptors; Estrogens; Estrogens - pharmacology; Estrogens - therapeutic use; Female; Genotype & phenotype; Growth factors; Humans; Inhibitors; Kinases; Lapatinib - pharmacology; Lapatinib - therapeutic use; Letrozole - pharmacology; MAP kinase; Metastases; Metastasis; Motility; Neoplasm Recurrence, Local - drug therapy; Nitriles - therapeutic use; Post-menopause; Prostate cancer; Pterocarpans; Targeted cancer therapy; Triazoles - pharmacology; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23052887

Aromatase inhibitors (AIs) are standard treatment for estrogen-dependent postmenopausal breast tumors; however, resistance develops leading to tumor relapse and metastasis. We previously demonstrated that glyceollin inhibits proliferation, survival, and migration of hormone-independent letrozole-resistant breast cancer. Since many AI-resistant tumors remain hormone-dependent, identifying distinctions between estrogen-receptor-positive (ER+) and ER-negative (ER-) AI-resistant tumor response to therapy is critical. We hypothesize that treating ER+ letrozole-resistant T47D breast cancer cells (T47DaromLR) with a combination of 10 μM glyceollin and 0.5 μM lapatinib (a dual EGFR/HER2 inhibitor) will decrease cell proliferation through induction of apoptosis. The T47DaromLR cells were found to overexpress HER2 and MAPK while maintaining aromatase and ER levels compared to their letrozole-sensitive (T47Darom) counterparts. In the absence of estrogen stimulation, glyceollin ± lapatinib had no effect on the proliferation of the T47Darom cells, while glyceollin treatment caused 46% reduction in the proliferation of T47DaromLR cells, which was further diminished when combined with lapatinib. While neither agent influenced cell migration, glyceollin and lapatinib reduced S and G2/M phase cell entry and exclusively induced apoptosis by 1.29-fold in the T47DaromLR cells. Taken together, these results suggest that glyceollins and lapatinib may have potential as a novel combination therapeutic approach for hormone-dependent, letrozole-resistant tumors.