Glyceollin triggers anti-proliferative effects in hormone dependent aromatase inhibitor resistant breast cancer cells through the induction of apoptosis

Authors: WALKER, RASHIDRA - Florida A & M University; PATEL, JANKIBEN - Florida A & M University; DAVIDSON, MICHAEL - Florida A & M University; WILLIAMS, CHRISTOPHER - Xavier University; PAYTON-STEWART, FLORASTINA - Xavier University; Boue, Stephen; BUROW, MATTHEW - Tulane University; TILGHMAN, SYREETA - Florida A & M University

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/3/2022
Publication Date: 3/7/2022
Citation: Walker, R., Patel, J., Davidson, M.A., Williams, C., Payton-Stewart, F., Boue, S.M., Burow, M., Tilghman, S. 2022. Glyceollin triggers anti-proliferative effects in hormone dependent aromatase inhibitor resistant breast cancer cells through the induction of apoptosis. International Journal of Molecular Sciences. 23. Article 2887. https://doi.org/10.3390/ijms23052887.
DOI: https://doi.org/10.3390/ijms23052887

Interpretive Summary: Aromatase inhibitors (AI) like letrozole 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 and negative AI-resistant tumor response to therapy is critical. We hypothesize that treating estrogen receptor letrozole-resistant breast cancer cells with a combination of glyceollin and lapatinib will decrease cell proliferation through induction of apoptosis. The cells were found to overexpress several genes while maintaining aromatase and estrogen levels compared to their letrozole-sensitive counterparts. In the absence of estrogen stimulation, glyceollin ± lapatinib had no effect on the proliferation of the breast cancer cells, while glyceollin caused a 46% reduction in the proliferation of breast cancer cells which was further diminished when combined with lapatinib. While neither agent influenced cell migration, glyceollin and lapatinib induced apoptosis by 1.29-fold in the cells. Taken together, these results suggest that glyceollin and lapatinib may have potential as a novel combination therapeutic approach for hormone-dependent, letrozole-resistant tumors.

Technical Abstract: Aromatase inhibitors (AI) 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 (ER+) positive 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 caused a 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 glyceollin and lapatinib may have potential as a novel combination therapeutic approach for hormone-dependent, letrozole-resistant tumors.