ABSTRACT

Triple-negative breast cancer (TNBC) displays an aggressive clinical course, heightened metastatic potential, and is linked to poor survival rates. Through its lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), this subtype remains unresponsive to traditional targeted therapies. Undesirable and sometimes life-threatening side effects associated with current chemotherapeutic agents warrant the development of more targeted treatment options. Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor implicated in breast cancer (BCa) progression, has proven to be an efficient approach to halt cancer growth in vitro and in vivo. Currently, there are no FDA-approved STAT3 inhibitors for TNBC. Although pimozide, a FDA-approved antipsychotic drug, has been attributed a role as a STAT3 inhibitor in several cancers, its role on this pathway remains unexplored in TNBC. As a “one size fits all” approach cannot be applied to TNBC therapies due to the heterogeneous nature of this aggressive cancer, we hypothesized that STAT3 could be a novel biomarker of response to guide pimozide therapy. Using human cell lines representative of four TNBC subtypes (basal-like 1, basal-like 2, mesenchymal-like, mesenchymal stem-like), our current report demonstrates that pimozide significantly reduced their invasion and migration, an effect that was predicted by STAT3 phosphorylation on tyrosine residue 705 (Tyr705). Mechanistically, phosphorylated STAT3 (Tyr705) inhibition resulting from pimozide treatment caused a downregulation of downstream transcriptional targets such as matrix metalloproteinase-9 (MMP-9) and vimentin, both implicated in invasion and migration. The identification of biomarkers of response to TNBC treatments is an active area of research in the field of precision medicine and our results propose phosphorylated STAT3 (Tyr705) as a novel biomarker to guide pimozide treatment as an inhibitor of invasion and migration.

摘要

三阴性乳腺癌（TNBC）表现出侵袭性的临床病程，转移潜力增加，并且与不良的生存率有关。由于缺乏雌激素受体（ER），孕激素受体（PR）和人表皮生长因子受体2（HER2）的表达，该亚型仍然对传统的靶向疗法无反应。与当前化学治疗剂相关的不希望的，有时甚至威胁生命的副作用保证了更多靶向治疗方案的发展。靶向信号转导和转录因子3（STAT3）的活化剂，在乳腺癌（BCA）进展牵连的转录因子，已被证明是一种有效的方法，以停止癌症生长的体外和体内。目前，尚无FDA批准的TNBC STAT3抑制剂。尽管已将FDA批准的抗精神病药pimozide归为几种癌症中STAT3抑制剂的作用，但在TNBC中仍未探讨其在该途径中的作用。由于这种侵袭性癌症的异质性，“一种千篇一律”的方法无法应用于TNBC治疗，因此我们假设STAT3可能是一种新的生物标志物，可指导匹莫唑治疗。我们的最新报告使用代表四种TNBC亚型的人类细胞系（基底样1，基底样2，间充质样，间充质干样），证明匹莫齐特显着减少了它们的侵袭和迁移，这是STAT3预测的酪氨酸残基705（Tyr705）上的磷酸化。机械上，吡虫嗪治疗引起的磷酸化STAT3（Tyr705）抑制作用导致下游转录靶标的下调，例如基质金属蛋白酶9（MMP-9）和波形蛋白，均与入侵和迁移有关。鉴定对TNBC治疗有反应的生物标志物是精密医学领域的一个活跃研究领域，我们的研究结果提出磷酸化的STAT3（Tyr705）作为一种新型生物标志物，可指导pimozide治疗作为入侵和迁移的抑制剂。