Nogo-B receptor increases the resistance to tamoxifen in estrogen receptor-positive breast cancer cells.

ABSTRACT: BACKGROUNDS:Tamoxifen is typically used to treat patients with estrogen receptor alpha (ER?)-positive breast cancer. However, 30% of these patients gain acquired resistance to tamoxifen during or after tamoxifen treatment. As a Ras modulator, Nogo-B receptor (NgBR) is required for tumorigenesis through the signaling crosstalk with epidermal growth factor (EGF) receptor (EGFR)-mediated pathways. NgBR is highly expressed in many types of cancer cells and regulates the sensitivity of hepatocellular carcinoma to chemotherapy. In this study, we found the expression of NgBR is increased in tamoxifen-resistant ER?-positive breast cancer cells. METHODS:Tamoxifen-resistant ER?-positive MCF-7 and T47D breast cancer cell lines were established by culturing with gradually increased concentration of 4-hydroxytamoxifen (4-OHT). The effects of NgBR on tamoxifen resistance was determined by depleting NgBR in these cell lines using previously validated small interfering RNA (siRNA). The effects of 4-OHT on cell viability and apoptosis were determined using well-accepted methods such as clonogenic survival assay and Annexin V/propidium iodide staining. The alteration of EGF-stimulated signaling and gene expression was determined by western blot analysis and real-time PCR, respectively. RESULTS:NgBR knockdown with siRNA attenuates EGF-induced phosphorylation of ER? and restores the sensitivity to tamoxifen in ER?-positive breast cancer cells. Mechanistically, our data demonstrated that NgBR knockdown increases the protein levels of p53 and decreases survivin, which is an apoptosis inhibitor. CONCLUSIONS:These results suggested that NgBR is a potential therapeutic target for increasing the sensitivity of ER?-positive breast cancer to tamoxifen.

SUBMITTER: Gao P 

PROVIDER: S-EPMC6134690 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature