Inhibitors of PI3K/ERK1/2/p38 MAPK Show Preferential Activity Against Endocrine-Resistant Breast Cancer Cells.

ABSTRACT

Current mainstream pharmacological options for the treatment of endocrine-resistant breast cancer have limitations in terms of their side effect profile and lack of discrimination between normal and cancer cells. In the current study, we assessed the responses of normal breast epithelial cells MCF10A, estrogen receptor-positive (ER+) MCF-7, and ER-silenced pII breast cancer cells to inhibitors (either individually or in combination) of downstream signaling molecules. The expression/activity of ERK1/2, p38 MAPK, and Akt was determined by Western blotting. Cell proliferation, motility, and invasion were determined using MTT, wound healing, and Matrigel assays, respectively. Morphological changes in response to variation in external pH were assessed by light microscopy. Our results demonstrated that the inhibitors of ERK1/2 (PD0325901), p38 MAPK (SB203580), and PI3K (LY294002) preferentially reduce breast cancer cell proliferation. In pII cells, they also reduced motility, invasion, and bleb formation induced by alkaline conditions. Combination treatment with lower concentrations of inhibitors was significantly more effective than single agents and was more effective against the cancer cell lines than the normal MCF10A. In contrast, the commonly used cytotoxic agent paclitaxel did not sufficiently discriminate between the MCF10A and the cancer cells. We concluded that combination therapy using ERK1/2 inhibitor and either p38 MAPK or PI3K inhibitor may provide a greater therapeutic benefit in treating breast cancer by specifically targeting cancer cells with lower doses of each drug than needed individually, potentially reducing unwanted side effects.