Being the most aggressive subtype of breast cancer (BCa), triple negative breast cancer (TNBC) is defined by its heightened metastatic potential and is associated with poor survival rates. Women diagnosed with TNBC do not respond to traditional targeted therapies because their tumors lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Due to undesirable side effects resulting from chemotherapeutics, the development of targeted treatment options for the TNBC patient population is warranted. Signal transducer and activator of transcription 3 (STAT3) has emerged as a promising therapeutic target in BCa and targeting this transcription factor has proven to be a viable approach to halt cancer growth in vitro and in vivo. Extensive research efforts are ongoing to bring STAT3 inhibitors to market for the treatment of TNBC. The FDA-approved antipsychotic drug pimozide has demonstrated efficacy as a STAT3 inhibitor in several cancers, however, its role on this pathway in TNBC remains unexplored. Due to intrinsic heterogeneity present among TNBCs and because a “one size fits all” approach cannot be applied to this aggressive cancer, we hypothesized that STAT3 could be a novel biomarker predictive of response to pimozide therapy in TNBC. Our research utilized human cell lines representative of four TNBC molecular subtypes: basal-like 1, basal-like 2, mesenchymal-like, and mesenchymal stem-like. Herein, we report that STAT3 phosphorylation on tyrosine residue 705 (Tyr705) dictated the ability of pimozide to significantly reduce the invasion and migration of TNBC subtypes. Mechanistically, downregulation of downstream STAT3 transcriptional targets implicated in invasion and migration, such as matrix metalloproteinase-9 (MMP-9) or vimentin, was observed upon inhibition of phosphorylated STAT3 (Tyr705) by pimozide treatment. Our results identify phosphorylated STAT3 (Tyr705) to be a promising and novel biomarker to guide pimozide therapy.
|Commitee:||Adejare, Adeboye, Suryanarayanan, Asha, Wang, Zhihong, Peethambaran, Bela|
|School:||University of the Sciences in Philadelphia|
|Department:||Pharmacology & Toxicology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/6(E), Dissertation Abstracts International|
|Keywords:||Biomarker, Drug repurposing, Pimozide, STAT3, Triple negative breast cancer|
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