EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells

• Published in: International journal of molecular sciences 2024-03, Vol.25 (6), p.3165
• Main Authors: Achounna, Angèle Sorel, Ordaz-Rosado, David, García-Quiroz, Janice, Morales-Guadarrama, Gabriela, Milo-Rocha, Edgar, Larrea, Fernando, Díaz, Lorenza, García-Becerra, Rocío
• Format: Article
• Language: English
• Subjects: Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Cancer; Cancer cells; Cancer therapies; Care and treatment; Cell growth; Cell Line, Tumor; Epidermal growth factor; Estrogen; Estrogen Antagonists - therapeutic use; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor Modulators - pharmacology; Estrogens; Female; Fulvestrant; Humans; Inhibitor drugs; Kinases; Lapatinib - pharmacology; Lapatinib - therapeutic use; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - metabolism; Targeted cancer therapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063165

HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.