Abnormal hormone functions were once thought to be the major reason for breast and prostate cancers. But Hongwu Chen's research is showing that a much broader network of cellular functions are actually at work.
Sex hormones – androgen and estrogen – are the elixirs that turn girls into women and boys into men. In cancer, however, these chemicals can go horribly awry and drive the formation of tumors in breast and prostate tissues. Cancers of the uterus and ovaries have also been linked to sex hormones and how they interact with other cells.
The role of sex-hormone signaling in cancer is an area of intense interest among scientists seeking a better understanding of the disease and potential targets for new treatments. One of the leaders in this area of research is Hongwu Chen, an associate professor of biochemistry and molecular medicine and co-leader of the molecular oncology research program at UC Davis Cancer Center.
A homegrown Aggie – he earned his doctorate in molecular and microbiology at UC Davis in 1995 – Chen has spent years studying the molecular foundations of hormone-related cancers. Recently, however, his research has led him to decipher a mechanism at work in a far wider variety of cancers and yielded promising targets for the next generation of chemotherapy drugs.
A molecular siren song
To better define those new drug targets, Chen is currently investigating a family of proteins that controls how often genes are expressed. Within human cells, DNA is wound in a structure called chromatin, like kite string around "packaging" proteins called histones. This packaged DNA must first be loosened up and made accessible before the information it encodes can be read.
The protein molecules in charge of unwinding and flagging a segment of DNA for expression are known as coregulators. These proteins can land on packaged DNA/chromatin and modify the chromatin structure, and they may also bind to one another to form complex, DNA transcription-controlling molecular devices. Chen is finding that coregulatory proteins constitute a major means of controlling gene expression.
"People used to think coregulatory proteins didn't really belong at the forefront of cancer biology, that they just played an accessory role," Chen says. "But we have come to the realization that coregulatory proteins can play the key role in derailing normal hormone functions."
Chen's interest in coregulatory proteins arose during his studies of hormones in breast and prostate cancers. He was particularly interested in a protein elevated in some breast cancers called ACTR. Previous researchers had found that ACTR interacts with estrogen receptors to trigger endless cell division and, thus, cancer.
Chen, expecting ACTR to operate only via hormone receptors, found the protein also caused proliferation among cells lacking estrogen receptors. In other words, ACTR didn't need a hormone receptor to do its dirty work.
"They don't function through the hormone receptor, but through one of the core cell circuits crucial for cancer development," Chen says.
Through further analysis, Chen found ACTR operates like the molecular version of a mermaid. Rather than enticing sailors to a briny death, ACTR lures away a molecule that keeps a tight lid on DNA transcription. Once this check on cell division is removed, a cell can begin the endless replications that cause cancer.
A new culprit in many cancers
Intrigued, Chen and his team dug deeper into how ACTR wreaked its havoc. They looked to see which genes ACTR activated. One of these – ANCCA – caught their attention.
Just by examining ANCCA's sequence, Chen could tell the protein encoded by ANCCA was worth a closer look. First, it contained an adaptor called a bromodomain that enabled it to bind to DNA-wrapping histones, making it a coregulatory protein. ANCCA also contained a structure that can metabolize ATP – the form of energy used in cells. This feature is common to enzymes that modify the shapes of other proteins.
"Based on these two characteristics, we felt this protein might play a very important role in the control of gene expression," Chen says.
ANCCA turned out to be amazingly similar to ACTR. Both are coregulators of hormone receptors for androgen and estrogen. But both can function in cells lacking hormone receptors too.
"It was like déjà vu," says Chen.
The discovery meant that ANCCA could be involved in cancers that aren't hormone-related. Chen and his team went on detecting the protein in cancer tissues, and found it not just in hormone-associated cancers such as prostate, ovarian and breast tumors, but in liver and lung tumors as well. His hunch proved to be correct.
"In each type of cancer cells we examined, we found ANCCA was crucial for their proliferation and survival," Chen says. "Thus, it may control a mechanism that is fundamental to many different cancers."
To date, they have analyzed hundreds of tumors for ANCCA. Levels of the protein were elevated in 60 to 70 percent of the breast cancer samples examined – an amazingly high fraction of the tumors. By comparison, the protein targeted by the drug Herceptin, widely prescribed to treat breast cancer, is elevated in about 30 percent of breast cancers.
"Even within, say, all prostate cancers, different things have gone wrong. So the impact of finding a coregulator like ANCCA that is common to the majority of cancers would be more significant," Chen says. "It offers a means to subvert a wide range of tumors with one swoop."
ANCCA also appears to have some value in predicting tumor aggression. Chen is finding that cells expressing ANCCA appear to replicate faster than other tumor cells.
"ANCCA may be a way for cells to overcome the proliferative hurdles that normally keep them under tight growth control," says Alexander Borowsky, a UC Davis associate professor of pathology and laboratory medicine and one of Chen's research collaborators.
Borowsky and Chen are studying how tumor cell differentiation affects cell replication rates. Cells that are less differentiated tend to replicate faster. They are also associated with more aggressive cancers with a worse prognosis. The researchers want to know how the interplay of cell differentiation and proliferation, or what Borowsky calls "the yin and yang" of cancer growth, influence tumor growth and patient outcomes.
Understanding the relationship between ANCCA and cell division may help doctors tailor cancer treatment regimens, Borowsky adds. Some types of chemotherapy are most effective in tissues that are replicating fast. So if ANCCA does correlate with cell division rates, a test for the protein could identify the tumors that should respond best to cytotoxic chemotherapy. Chen's team is currently testing this idea in the lab.
ANCCA's involvement in such a high percentage and wide range of cancers also makes it an alluring target for drug therapy.
In addition to its bromodomain and ATP binding site, the molecule contains a third area that allows it to clump together with other ANCCA molecules into oligomers. This gives scientists at least three places to target with drugs, which greatly increases the likelihood of finding methods to block ANCCA's effects.
"There are a lot of ways for small molecules to specifically target its function," Chen says.
Together with Ph.D. candidate Ekatarina Kalashnikova, Chen plans to publish the ANCCA over-expression in breast cancer results. His ACTR and ANCCA discoveries, however, have already generated a great deal of excitement in the endocrine and cancer research community.
"With such a high frequency of over-expression in cancer specimens and demonstrated potential to stimulate cell growth, ANCCA promises to be a valuable cancer marker," says Hsing-Jien Kung, professor of biochemistry and molecular medicine and director of basic sciences for UC Davis Cancer Center. "Dr. Chen has a knack for identifying important molecules to pursue for new therapies because of his insights and the careful, hard work of his lab. His current work exemplifies the type of translational research and integrative approaches our cancer center promotes."
If researchers can find pharmaceuticals to hijack ANCCA, many cancer patients could potentially benefit. Foremost among these could be breast and prostate cancer patients whose disease becomes hormone refractory. Such cancers rely on the presence of hormones to fuel growth at first, but eventually turn hormone-independent. The vast majority of breast and prostate tumors develop hormone resistance. And once hormone-elimination therapy no longer works on such cancers, relatively few options remain.
For these patients, the discovery of ANCCA could lead to a true lifeline.