Targeting JAK-STAT3 Signaling Pathway in HER-2 Overexpressing Breast Cancer Cells: A Novel Strategy toOvercome Trastuzumab Resistance

Although HER2-targeting antibody trastuzumab serves as an effective drug for patients withHER2-overexpressing breast cancer, the majority of patients develop resistance. This hasmotivated efforts toward finding underlying mechanisms to design new therapeutic strategiesfor breast cancer. Activation of the transcription factor STAT3 is thought to potentially promotedrug resistance in a variety of cancers. Here, we were aimed to evaluate whether JAKSTAT3signaling pathway can mediate the induced resistance to trastuzumab. In currentstudy, we investigated the effect(s) of STAT3 blockade on cell viability and cell death intrastuzumab- resistant breast cancer cells (SKBR3-R). Moreover, the level of phosphorylatedSTAT3 and downstream signaling pathways, namely Bcl-2, has also been investigated bywestern blot. Our results demonstrated that an elevation in STAT3 activity level wasassociated with a decrease in sensitivity to trastuzumab-induced cell death. However,treatment of these cells with STAT3 inhibitor (2.5ÂμM) and trastuzumab (10 Âμg/ml)recovered the trastuzumab sensitivity partially due to increased apoptosis through inductionof active caspase-3 production and decrease in Bcl2 levels among resistant cells. Our dataalso revealed that reduction in STAT-3 activation was accompanied with attenuation of HER-2 receptor expression in trastuzumab- resistant SKBR3 cancer cells. Taken together, ourresults suggest that activation of STAT3 might constitute a key element mediatingtrastuzumab resistance and thus, simultaneous targeting of both HER2 and STAT3 mayenhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breastcancer.

کلیدواژه ها:

Apoptosis ، Breast Cancer ، HER2 ، STAT3 ، Trastuzumab