A gene signature of loss of oestrogen receptor (ER) function and oxidative stress links ER-positive breast tumours with an absent progesterone receptor and a poor prognosis

An imbalance between pro-oxidants and antioxidants can lead to a state of oxidative stress. Yau and Benz [1] studied the subset of oestrogen (E)-responsive genes susceptible to modulation by oxidative stress. They identified an overlapping set of 891 E-related and oestrogen receptor (ER)-related probes in the MCF-7 ER+ breast cancer cell line associated with loss of E and ERα function (E/ER signature). They further compared the genes involved in this E/ER signature with probes from two different MCF-7 cell lines modulated by oxidative stress: (a) MCF-7 controls (Ox signature) and (b) MCF-7 cell lines with ERα knockdown (Ox' signature) leading to, respectively, the Ox-E/ER signature and Ox'-E/ER signature. The Ox-E/ER signature is a set of 62 unique genes, 46 of which are connected within networks linked through various kinases and growth factors (19) and oxidative signalling (16) and cell motility (11) pathways. Some of the genes in the signatures also imply, not surprisingly, that oxidative stress is associated with an impaired tumour necrosis factor-nuclear factor-kappa-B cell survival-death pathway and variable endocrine responsiveness of ER+ breast tumours.Only a third of genes involved in loss of ER function overlap with E-induced genes in MCF-7 breast cancer cells [2], which suggests that E withdrawal and ER function loss are not entirely reciprocal conditions relative to E stimulation. Only 8% of probes involved in ER function loss were affected by all oxidants, including Bcl2 but not progesterone receptor (PR) and GREB1, implying that PR loss is only a partial surrogate for increased oxidative stress [3]. Although there is little gene overlap with the prognostic molecular profile of ER+/PR- tumours in the luminal B subset as defined by Perou and colleagues [4] and Creighton and colleagues [5], these findings confirm that oxidative stress may be intrinsic to the highly proliferative subtype of luminal tumours [6]. Though ER+, they may be functionally analogou