Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells.
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.
Department of Pathology, Gittlen Cancer Research Foundation, Hershey Medical Center, H059, Pennsylvania State University, 500 University drive, Hershey, PA 17033, USA.
Nuray
N
Erin
Wei
W
Zhao
John
J
Bylander
Gary
G
Chase
Gary
G
Clawson
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D053179:Caspase 7 / Q000235:genetics; D045744:Cell Line, Tumor; D003714:Denervation; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006321:Heart / Q000294:innervation; D006338:Heart Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000556:secondary; D006868:Hydrolysis; D008168:Lung / Q000294:innervation; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009475:Neurons, Afferent / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D013373:Substance P / Q000378:metabolism; D013997:Time Factors
C086924:Elk3 protein, mouse; D008565:Membrane Proteins; D050783:Proto-Oncogene Proteins c-ets; D013373:Substance P; D053829:Amyloid Precursor Protein Secretases; D053179:Caspase 7; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D002211:Capsaicin