Serotonin Signals are Essential for the Survival of Breast Cancer Cells
Final rept. 1 Sep 2007-1 Sep 2008
DREXEL UNIV PHILADELPHIA PA
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Our hypothesis addresses the idea that serotonin is important for the growthsurvival of breast cancer cells. We tested 5 different types of breast cancer cell lines and have shown that the transcripts for both synthesizing and responding to serotonin signals are present in every type of cell, but each exhibits its own unique profile of expression. We removed serotonin from the cell culture medium and found that the cells transcriptionally responded to the presence or absence of exogenous serotonin through a feedback pathway. We found that several 5-HT receptor antagonists caused a loss of viability in breast cancer cells. The most potent inhibition was obtained by the use of a selective 5-HTsub 1B antagonist. The observed inhibition was significantly better than Tamoxifen. Mechanistically, we have shown that blocking the 1B receptor resulted in a loss of the Akt activity, leading to apoptosis. In addition, we found that highly proliferative cancer cells are more sensitive to 5-HTSUB 1B antagonist-induced cell death compared to resting normal cells. Normal MCF-10A cells grown in three dimensional basement membrane assays undergo minimal apoptosis following 5-HTSUB 1B antagonist treatment. In contrast, highly proliferative MCF-10A cells overexpressing the mutant form of ErbB2 are extremely sensitive to 5-HTSUB 1B antagonist-induced apoptosis. Taken together we believe that these data suggest that the 5-HTSUB 1B receptor plays a crucial role in the survival of breast cancer cells.
- Medicine and Medical Research