A new study from the University of Chicago1 comparing the effects of estrogen and retinoic acid on breast cancer cell genes shows that they have inverse effects- estrogen tips the scales towards cell proliferation and retinoic acid inhibits cellular growth.
The findings, reported in the June 25, 2009, issue of the journal Cell, may lead researchers to a whole new set of drug targets for breast cancer. The most widespread forms of breast cancer are driven by the female estrogen hormone. Estrogen and retinoic acid modify the expression of many of the same genes, and this control of gene expression regulates basic cellular processes, say the report’s authors. When regulation is unbalanced, it can lead to cancer.
“Understanding all the components of this process could be used against breast cancer care in three ways,” said study leader, Kevin White, PhD, director of the Institute for Genomics and System Biology at the University of Chicago. “It suggests new ways to think about preventing the disease in those at high risk. It offers molecular tools that could provide a more precise diagnosis and predict outcomes. It could also be used to enhance current therapies, making existing drugs, such as tamoxifen, that selectively block estrogen’s effects even more powerful, or even to develop new anti-cancer drugs.”
White studies nuclear receptors, a class of proteins that is found in cells controlling the response to various hormones. When a hormone enters a cell and hooks up with its receptor, the receptor changes the pattern of expression of specific genes, and often hundreds or more genes.
In this study, White and his colleagues Sujun Hua and Ralf Kittler looked at retinoic acid receptors. Retinoic acid is known for its anticancer effects and already is in use to treat a rare form of leukemia2. It has also been linked with anti-proliferative changes in breast cancer cells.
The team used two laboratory techniques; a process known as chromatin immunoprecipitation (ChIP), to see where the retinoic acid receptors bound to the genome, and micro-array gene-chip analysis, to measure expression levels of specific genes. This allowed them to map out all the genetic effects of retinoic acid and its receptors, in cell samples derived from patients with estrogen-related breast cancers.
They discovered that 39% of the gene regions bound by estrogen receptor alpha overlapped with those bound by retinoic acid. They also found that the binding of estrogen and retinoic acids receptors to target sites were often mutually exclusive, implying that the two hormones compete to activate or repress many of the same genes. Estrogen increased expression of 139 genes that retinoic repressed, and retinoic acid activated 185 genes that estrogen repressed. For about 140 genes, estrogen and retinoic acid had the same effect.
“Collectively, say the authors, “these findings indicate an extensive crosstalk” between effects of estrogen and retinoic acid. Regardless of the opposing effects, some versions of the estrogen and retinoic acid receptors actually activate each other. This provides “an additional level of control,” note the authors, “for achieving a balanced regulation of gene expression.”
Long Term Outcome Prediction
The competition between these two signals also provides a new tool to predict disease outcomes. Researchers compared the effects of retinoic acid on tissues from 295 breast cancer patients against results from their initial study using a typical breast cancer cell line. They found that the more responsive a tumor was to retinoic acid, the better the odds of long-term relapse-free breast cancer survival.
“Some of these genes may provide new drug targets,” White said. Some of them that act in response to retinoic acid were expressed even in difficult-to-treat tumors, such as those that do not have estrogen receptors or the molecule involved in so-called double- or triple-negative breast cancers.
“The goal would be to develop drugs that could activate these cancer-inhibiting targets,” said White. “Retinoic acid itself is probably not the solution because of its side effects and metabolic byproducts,” He cautioned, “but our results provide a molecular justification for finding ways to overcome its limitations in the clinic.”
1. Genomic Antagonism between Retinoic Acid and Estrogen Signaling in Breast Cancer– Hua, Sujun; Kittler, Ralf; White, Kevin P. doi:10.1016/j.cell.2009.04.043 (volume 137 issue 7 pp.1259 – 1271)
2. Tallman MS (February 2002). “Retinoic acid syndrome: a problem of the past?”. Leukemia 16 (2): 160–1. doi:10.1038/sj.leu.2402344. PMID 11840279
Image: Adrian Wressell, Heart of England NHSFT. Wellcome Images