Scientists have linked estrogen to the development of a particularly aggressive type of tumour that accounts for half of all prostate cancer cases.
Researchers from Weill Cornell Medical College have found that hormonal signals from estrogen encourage two genes, known as TMPRSS2 and ERG, to fuse, which then causes the tumour to form.
"Interfering with this gene fusion will be crucial in the search for drugs that fight the disease," the study's senior author, Dr. Mark A. Rubin of Weill Cornell Medical College, said in a statement.
"Based on our new data, we now believe that inhibiting estrogen may be one way of doing so."
This study, which analyzed more than 455 prostate cancer samples, was conducted by Rubin along with scientists from Brigham and Women's Hospital, the Massachusetts Institute of Technology and Harvard University in Boston. The findings are published in the online edition of the Journal of the National Cancer Institute.
Doctors have long known that male hormones are associated with prostate cancer, and androgen-deprivation therapy is a common treatment for the disease.
However, this treatment is not always successful, so Rubin and his colleagues decided to investigate other hormonal pathways that can lead to prostate cancer.
Abstract:
Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer
Sunita R. Setlur, Kirsten D. Mertz, Yujin Hoshida, Francesca Demichelis, Mathieu Lupien, Sven Perner, Andrea Sboner, Yudi Pawitan, Ove Andr��n, Laura A. Johnson, Jeff Tang, Hans-Olov Adami, Stefano Calza, Arul M. Chinnaiyan, Daniel Rhodes, Scott Tomlins, Katja Fall, Lorelei A. Mucci, Philip W. Kantoff, Meir J. Stampfer, Swen-Olof Andersson, Eberhard Varenhorst, Jan-Erik Johansson, Myles Brown, Todd R. Golub, Mark A. Rubin
Background: The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion.
Methods: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians' Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided.
Results: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ER�� agonist (ER�� agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ER agonist treatment (ER agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ER�� agonist treatment (fold change over internal control, ER�� agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ER agonist treatment (ER agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold).
Conclusions: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
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