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Title: NUMERICAL DECONVOLUTION OF CDNA MICROARRAY SIGNAL

Author
item ROSENFELD, SIMON - NCI,NIH, BETHESDA,MD
item Wang, Thomas - Tom
item KIM, YOUNG - NCI,NIH, BETHESDA,MD
item MILNER, JOHN - NCI,NIH, BETHESDAY,MD

Submitted to: New York Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2004
Publication Date: 7/6/2004
Citation: Rosenfeld, S., Wang, T.T.Y., Young, K., and Milner, J. Numerical deconvolution of cDNA microarray signal, Ann. N.Y. Acad. Sci., 1020:110-123, 2004.

Interpretive Summary: Exposure to steroid hormones such as androgen and estrogen is considered risk factor for development of prostate cancer. However, the molecular effects of steroid hormones on prostate cancer cell remain largely unknown. To better design preventive strategy, it would be important to better understand the molecular events modulated by these hormones. In this study we examined the effects of estrogen on human prostate cancer cells. We found exposure of prostate cancer cell to estrogen can lead to a stimulation of cell proliferation. We also demonstrated that estrogen appeared to activate several genes that also respond to androgen. This effect of estrogen is mediated through the estrogen receptor beta. This is a first demonstration of a cross talk between these two hormone-mediated pathways through specific genes. This work provide novel information for cancer research scientist regarding molecular targets and mechanism(s) of action of steroid hormones and will serve as important bases for future design of cancer preventive strategy. This information will benefit basic research scientists interested in gene regulation, as well as cancer prevention research scientists interested in molecular mechanisms in the regulation in cancer cells.

Technical Abstract: The molecular mechanism of action of estrogens in normal prostate physiology and prostate cancer development remains unclear. To better understand the molecular effects of estrogen on prostate carcinogenesis, we examined the effect of 17'-estradiol on the androgen-responsive LNCaP human prostate cancer cell line. We confirmed that LNCaP cells express estrogen receptor-' (ER-'', but not ER-', and found that exposure of LNCaP cells to 17'-estradiol led to a dose- and time-dependent increase in LNCaP cell growth. These effects of 17'-estradiol on LNCaP cell proliferation were blocked by the pure antiestrogen ICI 182,780. This proliferative effect of 17'-estradiol correlated with differential induction of several androgen-responsive genes (ARGs), including prostate-specific antigen (PSA), by 17'-estradiol. Consistent with involvement of ER-', the induction of ARG mRNA levels by 17'-estradiol was also attenuated by ICI 182,780. In further support of estrogen/ER-'-mediated control, multiple putative estrogen responsive elements (EREs) were identified in the promotor region of the estrogen-inducible ARGs with two independent genomic analysis algorithms. These results provide the first mechanistic evidence supporting a direct effect of estrogen, mediated through ER-'-dependent pathways, on specific molecular targets in human prostate cancer cells.