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Oxidative stress can modify estrogen receptor (ER) structure and function, including induction of progesterone receptor (PR), altering the biology and clinical behavior of endocrine responsive (ER-positive) breast cancer.    Methods  To investigate the impact of oxidative stress on estrogen/ER-regulated gene expression, RNA was extracted from ER-positive/PR-positive MCF7 breast cancer cells after 72 hours of estrogen deprivation, small-interfering RNA knockdown of ER-α, short-term (8 hours) exposure to various oxidant stresses (diamide, hydrogen peroxide, and menadione), or simultaneous ER-α knockdown and oxidant stress. RNA samples were analyzed by high-throughput expression microarray (Affymetrix), and significance analysis of microarrays was used to define gene signatures responsive to estrogen/ER regulation and oxidative stress. To explore the association of these signatures with breast cancer biology, microarray data were analyzed from 394 ER-positive primary human breast cancers pooled from three independent studies. In particular, an oxidant-sensitive estrogen/ER-responsive gene signature (Ox-E/ER) was correlated with breast cancer clinical parameters and disease-specific patient survival (DSS).    Results  From 891 estrogen/ER-regulated probes, a core set of 75 probes (62 unique genes) responsive to all three oxidants were selected (Ox-E/ER signature). Ingenuity pathway analysis of this signature highlighted networks involved in development, cancer, and cell motility, with intersecting nodes at growth factors (platelet-derived growth factor-BB, transforming growth factor-β), a proinflammatory cytokine (tumor necrosis factor), and matrix metalloproteinase-2. Evaluation of the 394 ER-positive primary breast cancers demonstrated that Ox-E/ER index values correlated negatively with PR mRNA levels ( r  p  = -0.2;  P  = 0.00011) and positively with tumor grade ( r  p  = 0.2;  P  = 9.741 × e -5 ), and were significantly higher in ER-positive/PR-negative versus ER-positive/PR-positive breast cancers ( t -test,  P  = 0.0008). Regardless of PR status, the Ox-E/ER index associated with reduced DSS ( n  = 201; univariate Cox,  P  = 0.078) and, using the optimized cut-point, separated ER-positive cases into two significantly different DSS groups (log rank,  P  = 0.0009).    Conclusion  An oxidant-sensitive subset of estrogen/ER-responsive breast cancer genes linked to cell growth and invasion pathways was identified and associated with loss of PR and earlier disease-specific mortality, suggesting that oxidative stress contributes to the development of an aggressive subset of primary ER-positive breast cancers.

breast cancer research

Genes responsive to both oxidant stress and loss of estrogen receptor function identify a poor prognosis group of estrogen receptor positive primary breast cancers