Oxidative stress pathways highlighted in tumor cell immortalization: association with breast cancer outcome

Abstract

An improved understanding of cell immortalization and its manifestation in clinical tumors could facilitate novel therapeutic approaches. However, only rare tumor cells, which maintain telomerase expression in vitro, immortalize spontaneously. By expression-profiling analyses of limited-life primary breast tumor cultures pre-and posthTERT transduction, and spontaneously immortalized breast cancer cell lines, we identified a common signature characteristic of tumor cell immortalization. A predominant feature of this immortalization signature (ImmSig) was the significant overexpression of oxidoreductase genes. In contrast to epithelial cells derived from low histologic grade primary tumors, which required hTERT transduction for the acquisition of ImmSig, spontaneously immortalizing high-grade tumor cultures displayed similar molecular changes independent of exogenous hTERT. Silencing the hTERT gene reversed ImmSig expression, increased cellular reactive oxygen species levels, altered mitochondrial membrane potential and induced apoptotic and proliferation changes in immortalized cells. In clinical breast cancer samples, cell-proliferation-pathway genes were significantly associated with ImmSig. In these cases, ImmSig expression itself was inversely correlated with patient survival (P ¼ 0), and was particularly relevant to the outcome of estrogen receptor-positive tumors. Our data support the notion that ImmSig assists in surmounting normal barriers related to oxidative and replicative stress response. Targeting a subset of aggressive breast cancers by reversing ImmSig components could be a practical therapeutic strategy.

Bisphenol A Induces a Profile of Tumor Aggressiveness in High-Risk Cells from Breast Cancer Patients

“…This is likely due to the fact that gene expression profiles were compared here between cell cultures of equivalent growth rate. A similar observation was made in the identification of a cancer cell immortalization signature based on the comparison of finite life (but proliferating) and immortalized primary breast tumor cells (20). Thus, the association of CPRP-BPA with breast cancer aggressiveness does not merely reflect a correlation between proliferating cells in vitro and those in highgrade tumors.…”

Tumor cell redox state and mitochondria at the center of the non-canonical activity of telomerase reverse transcriptase

“…But does telomerase play a reverse role and modulate oxidative stress? Evidence does seem to point in that direction as several recent studies reported improved response against oxidative stress in hTERT expressing cells (Armstrong et al, 2005;Beliveau and Yaswen, 2007;Dairkee et al, 2007;Lee et al, 2005;Lorenz et al, 2001;Mondello et al, 2006). A recent study with telomerase expressing MRC-5 lung fibroblasts demonstrated a significant translocation of hTERT to the mitochondria following oxidative stress, which was followed by lower mitochondrial DNA damage, reduced mitochondrial peroxide levels and an increase in mitochondrial membrane potential (Ahmed et al, 2008).…”

hTERT Overexpression Alleviates Intracellular ROS Production, Improves Mitochondrial Function, and Inhibits ROS-Mediated Apoptosis in Cancer Cells

“…Despite convincing evidence that cellular redox status impacts hTERT biology, the effect of hTERT on cancer cell redox milieu remains less well defined. In this regard, studies have suggested a protective cellular response against oxidative stress in hTERT overexpressing cells (13)(14)(15). In addition, reports have also suggested that hTERT expression positively impacts mitochondrial function by improving its calcium buffering capacity and reducing O 2 À production (16).…”