Novel therapeutic combination targets the growth of letrozole resistant breast cancer through decreased cyclin B1

Authors: PATEL, JANKIBEN - Florida A & M University; BANJARA, BIPIKA - Florida A & M University; OHEMENG, AFIA - Florida A & M University; DAVIDSON, MICHEAL - Florida A & M University; Boue, Stephen; BURROW, MATTHEW - Tulane University; TILGHMAN, SYREETA - Florida A & M University

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/24/2023
Publication Date: 3/28/2023
Citation: Patel, J., Banjara, B., Ohemeng, A., Davidson, M.A., Boue, S.M., Burrow, M., Tilghman, S. 2023. Novel therapeutic combination targets the growth of letrozole resistant breast cancer through decreased cyclin B1. Nutrients. 15:1632. https://doi.org/10.3390/nu15071632.
DOI: https://doi.org/10.3390/nu15071632

Interpretive Summary: As breast cancer cells transition from letrozole (hormone based chemotherapy)-sensitive to letrozole-resistant they overexpress several proteins while acquiring enhanced motility that are attenuated and reversed by soybean glyceollin treatment. Interestingly, a soybean phytochemical called glyceollin inhibits the proliferation and tumor progression of triple negative breast cancer and estrogen (hormone)-independent breast cancer cells, however it is unlikely that a single phytochemical would effectively target resistant metastatic breast cancer in the clinical setting. Since our previous report indicated that the combination of lapatinib (anticancer drug) and glyceollin induced apoptosis (cell death) in hormone-dependent resistant breast cancer cells, we hypothesized that combination therapy will also be beneficial for hormone independent letrozole-resistant breast cancer cells compared to aromatase inhibitor-sensitive breast cancer cells by decreasing the expression of proteins associated with proliferation and cell cycle progression. This phenomenon may represent a unique opportunity to design novel combinatorial therapeutic approaches to target hormone refractory breast tumors

Technical Abstract: As breast cancer cells transition from letrozole-sensitive to letrozole-resistant they overexpress EGFR (epidermal growth factor), MAPK (mitogen-activated protein kinase), and HER2 (human epidermal growth factor receptor 2) while acquiring enhanced motility and EMT-like characteristics that are attenuated and reversed by glyceollin treatment. 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 will 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.