Yau, C. & Benz, C. C. Genes responsive to both oxidant stress and loss of estrogen receptor (ER) function identify a poor prognosis group of ER-positive primary breast cancers. Breast Cancer Res. 10, R61

Buck Institute for Age Research, Redwood Boulevard, Novato, California 94945, USA.
Breast cancer research: BCR (Impact Factor: 5.49). 07/2008; 10(4):R61. DOI: 10.1186/bcr2120
Source: PubMed


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.
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-alpha, short-term (8 hours) exposure to various oxidant stresses (diamide, hydrogen peroxide, and menadione), or simultaneous ER-alpha 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).
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-beta), 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 (rp = -0.2; P = 0.00011) and positively with tumor grade (rp = 0.2; P = 9.741 x 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).
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.

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    • "On the other hand, this fact suggests that cancer can potentially induce oxidative damage in surrounding normal cells. Therefore, nontransformed epithelial cells located adjacently to the tumoral tissue may experience variable concentrations of RS generated by the constitutive activation of mitogenic pathways arising from surrounding tumor cells [8]; however, the impact of this event on the homeostasis "
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    • "These observations, in combination with cell culture data (Fig. 1A), demonstrated that HOXC10 is overexpressed in breast cancer and potentially upregulated in placental choriocarcinoma cells. Notably, MCF7 and T47D are well-known ER-positive breast cancer cell lines and have been widely used for estrogen-related experiments (Jansson et al. 2006, Yau & Benz 2008). Similarly, JAR cell is a placental choriocarcinoma cell line and placenta is known to produce various steroid hormones that are circulated to fetus as well as to the mother (Strauss et al. 1996). "
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GPNMB is a type I transmembrane, cell surface expressed protein with an extracellular RGD and PKD domains and a cytoplasmic hemITAM signaling motif that had not previously been implicated in breast cancer. We demonstrate that ectopic GPNMB expression was sufficient to promote migration and invasion of breast cancer cells in vitro and the formation of bone metastases in vivo.Subsequently, we analyzed GPNMB mRNA and protein expression levels in hundreds of breast tumors and found that GPNMB expression positively correlates with increased risk of metastasis and shorter overall survival times. We have also demonstrated that GPNMB is most commonly expressed in breast tumors belonging to the triple negative subtype, for which there are no targeted therapies currently available. We showed for the first time that CDX-011, a GPNMB-targeted monoclonal antibody-drug conjugate, was capable of killing GPNMB-expressing breast cancer cells in vitro and inducing tumor regression in vivo. Finally, we investigated the effects of GPNMB on primary tumor progression and found that it inhibits tumor cell apoptosis while enhancing angiogenesis and tumor growth in vivo. We demonstrate that the extracellular domain (ECD) of GPNMB can be proteolytically cleaved and shed from the surface of breast cancer cells, which is mediated by ADAM10. We postulated that the shed extracellular domain (ECD) of GPNMB might be responsible for some of its pro-angiogenic effects and showed that this ECD was indeed capable of inducing endothelial cell migration in vitro.The body of work described in this thesis is the first to identify GPNMB as a functional mediator of breast cancer growth and metastasis and to validate it as an important clinical target in human breast cancer. Le cancer du sein est le cancer le plus fréquemment diagnostiqué et la seconde cause de mortalité associée au cancer chez les femmes canadiennes. 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