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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.

Previously, we showed that caveolin-1 (Cav-1) expression is down-regulated in human breast cancer-associated fibroblasts. However, it remains unknown whether loss of Cav-1 occurs in the breast tumor stroma in vivo. Here, we immunostained a well-annotated breast cancer tissue microarray with antibodies against Cav-1 and scored its stromal expression. An absence of stromal Cav-1 was associated with early disease recurrence, advanced tumor stage, and lymph node metastasis, resulting in a 3.6-fold reduction in progression-free survival. When tamoxifen-treated patients were selected, an absence of stromal Cav-1 was a strong predictor of poor clinical outcome, suggestive of tamoxifen resistance. Interestingly, in lymph node-positive patients, an absence of stromal Cav-1 predicted an 11.5-fold reduction in 5-year progression-free survival. Clinical outcomes among patients positive for HER2, and patients triple-negative for estrogen receptor, progesterone receptor and HER2, were also strictly dependent on stromal Cav-1 levels. When our results were adjusted for tumor and nodal staging, an absence of stromal Cav-1 remained an independent predictor of poor outcome. Thus, stromal Cav-1 expression can be used to stratify human breast cancer patients into low-risk and high-risk groups, and to predict their risk of early disease recurrence at diagnosis. Based on related mechanistic studies, we suggest that breast cancer patients lacking stromal Cav-1 might benefit from anti-angiogenic therapy in addition to standard regimens. We conclude that Cav-1 functions as a tumor suppressor in the stromal microenvironment.

Here we used the Met-1 cell line in an orthotopic transplantation model in FVB/N mice to dissect the role of the Cav-1(P132L) mutation in human breast cancer. Identical experiments were performed in parallel with wild-type Cav-1. Cav-1(P132L) up-regulated the expression of estrogen receptor-alpha as predicted, because only estrogen receptor-alpha-positive patients have been shown to harbor Cav-1(P132L) mutations. In the context of primary tumor formation, Cav-1(P132L) behaved as a loss-of-function mutation, lacking any tumor suppressor activity. In contrast, Cav-1(P132L) caused significant increases in cell migration, invasion, and experimental metastasis, consistent with a gain-of-function mutation. To identify possible molecular mechanism(s) underlying this invasive gain-of-function activity, we performed unbiased gene expression profiling. From this analysis, we show that the Cav-1(P132L) expression signature contains numerous genes that have been previously associated with cell migration, invasion, and metastasis. These include i) secreted growth factors and extracellular matrix proteins (Cyr61, Plf, Pthlh, Serpinb5, Tnc, and Wnt10a), ii) proteases that generate EGF and HGF (Adamts1 and St14), and iii) tyrosine kinase substrates and integrin signaling/adapter proteins (Akap13, Cdcp1, Ddef1, Eps15, Foxf1a, Gab2, Hs2st1, and Itgb4). Several of the P132L-specific genes are also highly expressed in stem/progenitor cells or are associated with myoepithelial cells, suggestive of an epithelial-mesenchymal transition. These results directly support clinical data showing that patients harboring Cav-1 mutations are more likely to undergo recurrence and metastasis.

The ability of cells to escape apoptosis is critical for carcinogenesis as well as resistance to radiation and chemotherapy. ARC (Apoptosis Repressor with CARD (caspase recruitment domain)) is an unusual inhibitor of apoptosis in that it antagonizes both the extrinsic (death receptor) and intrinsic (mitochondrial/ER) apoptosis pathways. ARC is expressed predominantly in terminally differentiated cells such as cardiac and skeletal myocytes and neurons. Recently, however, the abundance of ARC was noted to be markedly increased in the epithelium of primary human breast cancers compared with benign breast tissue and to confer chemo- and radiation-resistance. Whether the induction of ARC is specific to breast cancer or a more general feature of neoplasia remains unknown. In this study, we assessed the abundance and subcellular localization of ARC in 21 human colon cancer cell lines and in 44 primary human colon adenocarcinomas and adjacent benign colonic tissue. ARC was present at high levels in most colon cancer cell lines and in almost all primary colon cancers compared with corresponding controls. Levels of ARC in the cytoplasm were increased in well, moderately, and poorly differentiated cancers compared with benign tissue, while levels of nuclear ARC were increased only in moderately differentiated tumors. Moreover, epithelial cancers of the ovary and cervix exhibited increased ARC abundance compared with controls. These results demonstrate that ARC is a novel marker of human colon cancer and suggest that it may be a general feature of epithelial cancers.