The majority of breast cancers are estrogen receptor positive (ER+) and utilize estrogen to promote cell proliferation. Thus, the ER has been the target of many therapies. While this strategy has been successful, the long‐term use of antiestrogen therapies, such as tamoxifen (Tam), frequently results in Tam resistance (Tam‐R). Tam‐R cells may proliferate due to the activation of the phosphatidylinositol‐3 kinase (PI3K) and the mitogen‐activated protein kinase (MAPK) pathways. Targeting these proliferation and survival pathways after the development of resistance is critical for the treatment of drug‐resistant cancers. We have identified the flavanone Naringenin (Nar) as an inhibitor of both the PI3K and MAPK pathways. Here, we show that Nar impairs cell proliferation and induces apoptosis of Tam‐R MCF‐7 breast cancer cells. We also demonstrate that Nar treatment reduced the levels of both ERK and AKT in Tam‐R cells. Furthermore, Nar treatment localized ERα to a perinuclear region in Tam‐R cells. Nar may function by inhibiting both the PI3K and MAPK pathways as well as localizing ERα to the cytoplasm to impair cell proliferation of Tam‐R MCF‐7 cells. These studies provide insight into the molecular mechanisms involved in cell proliferation of Tam‐R breast cancer cells.
Part of the book: Breast Cancer