Role of TAAR1 in breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive cancer subtype with poor patient survival due to high rates of metastasis and a lack of targeted treatments. Recently, a positive correlation between Trace Amine-Associated Receptor 1 (TAAR1) expression and breast cancer (BC) survival was reported, suggesting a possible protective role of the receptor in this disease state. Further, the TAAR1 agonist T1AM has been shown to induce inhibition of cancer cell proliferation and growth, but T1AM-TAAR1 mechanisms are not yet understood in this context. This dissertation was designed to systematically assess TAAR1 signaling effects on a range of malignancy-related cellular functions in BC. A panel of molecularly and phenotypically diverse human BC cell lines was assessed to characterize TAAR1 expression and validate use in functional studies. My studies identified two cell lines exhibiting distinct patterns of TAAR1 localization: MDA-MB-231 and MCF-7 cells. These cells preferentially express TAAR1 on the cell surface and intracellularly, respectively. This dichotomy was chosen to assess whether availability of cell surface T1AM binding sites translated into functional differences in cancer cell functions. My studies revealed that congruent with TAAR1 expression patterns, MDA-MB-231 cells were more sensitive to T1AM-induced cAMP accumulation, cell-killing, and inhibition of the metastatic phenotype than MCF-7 cells. TAAR1 activation with T1AM significantly reduced the migratory capacity of TNBC cells in-vitro and drug preincubation enhanced these effects, suggesting there may be modulation of downstream gene targets to modulate metastatic capacity. Agonist induced morphological changes to MDA-MB-231 cells resembled those undergone during transition from metastatic mesenchymal to epithelial phenotypes and may explain the protective effect reported in the literature. MCF-7 cells were largely devoid of significant responses, supporting the hypothesis that TAAR1 activation and its subcellular localization is indeed driving these anti-cancer effects. Taken together, the data generated in this dissertation provide evidence for TAAR1 modulation of cellular functions critical to metastatic progression and identify a novel receptor target for TNBC.--Author's abstract