Gene signature for endocrine resistance studied

[Hopeful]

http://breast-cancer-research.com/co...df/bcr2913.pdf

Collectively, our observations in primary breast tumors and in breast cancer cells in vitro provide evidence that the overexpression of 14-3-3ζ and the associated 14-3-3ζ gene signature identify a subgroup of ER positive tumors most likely to be resistant to endocrine therapies and to show early recurrence. In addition, our studies reveal that 14-3-3ζ expression can also be increased as a consequence of tamoxifen treatment, and therefore, ironically, that tamoxifen itself, through up-regulation of 14-3-3ζ, may be contributing to the development of endocrine resistance.

Broad impact of 14-3-3ζ on key cellular activities and signaling pathways

14-3-3ζ status had a great impact on cell signaling pathways and the molecular properties of breast cancer cells. With high 14-3-3ζ, cells showed enhanced activation of EGFR, HER2, MAPK, and AKT, and increased anchorage-dependent and independent growth. These activities were suppressed by down-regulation of 14-3-3ζ. Thus, 14-3-3ζ increases signaling through a variety of growth factor receptors and protein kinase pathways, stimulating a more robust and temporally prolonged activation of these pathways to promote survival and anti-apoptotic signaling, and enhance the endocrine resistance of breast cancer cells.

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