Model illustrating how FOXA1 defines subdomains of action in breast cancer cells. Green arrows represent transcription activity of ERα and FOXA1; dashed blue arrow indicates the action of FOXA1 as a modulator of ERα binding to a subset of promoters. FOXA1 thus grants permission to ERα to regulate a subset of the hormone response.

Scientists have long thought that gene programs were regulated by different physiological processes throughout the body and were pre-determined and relatively fixed for every specialized cell.

But a new study by researchers from the University of California, San Diego School of Medicine reveals the unsuspected plasticity of some of these gene programs.

Their findings, to be published in the May 15 advanced on-line edition of journal Nature, show the existence of distinct gene programs that can respond differently, depending on intracellular conditions.

The study helps explain why the same signaling event – such as a cellular response to circulating hormones – can be beneficial for normal development, but become cancerous when combined with other genetic lesions.

The UCSD scientists found that the response to the hormone androgen in prostate epithelial cells can lead to dramatic reprogramming into alternative gene programs and profiles. This flexibility could be the basis for the formation and progression of at least some forms of cancer, as well as for cell differentiation needed for normal development.

From a patient perspective, the results of this study help explain how hormone therapies, applied to prostate cancer in order to block hormone-regulated tumors, can escape treatment and become more malignant.

"Aggressive cell types, such as found in prostate cancer, basically learn to ignore hormone therapy," said co-principal investigator Xiang-Dong Fu, PhD, professor in the UCSD Department of Cellular and Molecular Medicine, who collaborated with co-principal investigator Michael G. Rosenfeld, MD, professor in the UCSD Department of Medicine and a Howard Hughes Medical Institute investigator.

UCSD researchers looked at the down-regulation in the expression of a single transcription factor, FoxA1, which is a bad sign in certain advanced prostate tumors. They found that FoxA1, which is needed for normal prostate development, can also facilitate as well as restrict the binding of a receptor controlling its hormone response. Consequently, down-regulating FoxA1 triggers reprogramming of the cells' hormonal response.

Other cancer-associated events, such as specific androgen receptor (AR) gene mutations, appear capable of creating similar effects. This massive switch in AR binding to a distinct group of enhancers (pre-established regulatory elements in the human genome) is what may allow cancer cells to "reprogram" themselves.

These findings suggest that therapies designed to stop the switch between different gene programs may be more effective than simply blocking the hormonal response, according to co-first author Dong Wang, PhD and co-first author and co-principal investigator Ivan Garcia-Bassets, PhD, research assistant professor in the UCSD Division of Endocrinology and Metabolism, Department of Medicine.

Additional contributors to the study include co-first author Chris Benner, PhD, Jinsong Qiu, PhD, Minna U. Kaikkonen, PhD, and Christopher K. Glass, MD, PhD, UCSD Department of Cellular and Molecular Medicine; Wenbo Li, PhD, Kenneth A. Ohgi, UCSD Department of Medicine, Howard Hughes Medical Institute; Xue Su and Wen Liu, Howard Hughes Medical Institute and UCSD graduate program in biology; and Yiming Zhou, PhD, Dignomics LLC, Malden, MA.

This comprehensive study of the mechanism underlying gene expression reprogramming was supported by funding from the Department of Defense, the National Institutes of Health, the National Cancer Institute, the Prostate Cancer Foundation and the Howard Hughes Medical Institute.

Original article:

http://www.eurekalert.org/pub_releases/2011-05/uoc--poh051211.php