Response of triple negative breast cancer cells to extracellular nucleotides
Date
2012
Authors
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Publisher
University of Delaware
Abstract
Inflammatory breast cancer (IBC) and triple negative non -IBC are two highly aggressive forms of breast cancer that are difficult to treat and have high incidences of recurrence. Most IBC are also triple negative in nature and have a molecular profile that classifies them as basal cell type. Despite some similarities, these distinct forms of breast cancer have phenotypic differences that set them apart. The P2Y receptors are a class of G protein coupled receptors that control key cellular processes such as growth, proliferation, and migration in both normal and pathological states. The eight known subtypes of the P2Y receptors have been identified in several cancers and can vary in expression depending on the cancer type. In this study, we hypothesize that P2Y receptors promote the aggressive phenotype of both triple negative inflammatory and non-inflammatory breast cancer. As the exact receptor subtypes have been characterized in only a few cancer cell lines, in this study we compare RNA expression profiles of P2Y receptors from a triple-negative inflammatory breast cancer cell line (SUM149) and triple-negative non-inflammatory breast cancer cell lines (GI101A and GILM2, an isogeni c progression of the GI-101A cells). Once the receptor subtypes are found, the specific agonists for each could be identified through the use of an extensive database that details the pharmacology of these receptors. We demonstrated that treating the cells with the relevant agonists had a differential effect with respect to proliferation and invasion. Furthermore, in the process of identifying the most effective ligands, we discovered that adenosine had a considerable negative effect on growth in the SUM 149 cells that was not seen in the non-IBC cell lines. This data led us to believe that there may be a difference in adenosine receptor expression on these cells. Like the purinergic receptors, adenosine receptors have been implicated in the development an d progression of various types of cancers. We show that our three cell lines in fact express only the same adenosine receptor subtype, A1. It was noted, however, that the levels of RNA expression vary between them. This may, in part, explain some of the differential responses we observed among these cells. The treatment of cancer with exogenous nucleotides like ATP has shown some initial promise in the clinic. Considerably aggressive, inflammatory breast cancer and triple negative breast cancers are particularly deadly because of the high rate of treatment failure and recurrence. This study examines the response of triple negative breast cancer cells to extracellular nucleotides/nucleosides. Our data show the antiproliferative effects of ATP and its derivatives, giving hope that, perhaps one day, it may be used as an adjuvant therapy for these devastating cancers.