Discovery of how prolactin travels to gene’s machinery helps explain its role in breast cancer

Prolactin, a naturally occurring peptide hormone needed for milk production following pregnancy, has been found to play a major role in the development and spread of breast cancer. More recently, Dr. Charles Clevenger, the same researcher who first demonstrated the scope and mechanism of prolactin’s role in cancer, has discovered that prolactin functions directly inside the cell, not merely by sending signals across the cell membrane as had been assumed for it and all other peptide hormones.

Dr. Clevenger also has discovered how prolactin is able to travel across the cell membrane and directly into the DNA machinery of the cell. These findings suggest a pathway through which new therapies could block the growth and spread of breast cancer — and offer a new paradigm for how other hormones function, not just in breast cancer but in a number of other diseases.

The University of Pennsylvania researcher describes his research at the Experimental Biology 2003 meetings in San Diego. He will be honored by the American Society of Investigative Pathology, at the EB 2003 meeting, with the Pfizer Outstanding Investigator Award. The award honors a decade of steady unraveling, by Dr. Clevenger, of how prolactin works in breast cancer, including this most recent discovery.

Although scientists recognized prolactin was involved with breast cancer in rats as early as the 1970s, they focused solely on the hormone produced by the pituitary gland in the brain. Human trials based on this assumption failed miserably. But in the 1990s, using greatly improved technology and techniques, Dr. Clevenger was able to show that breast tissue itself produces prolactin in significant quantities and that more than 95 percent of all breast cancers express the prolactin receptor, meaning prolactin was active in the tumors. At the same time, a large population study of nurses had found that women with higher levels of prolactin were at greater risk for breast cancer.

Soon thereafter, Dr. Clevenger was able to show how prolactin organized the breast cancer cells to move from the breast to other parts of the body.

His most recent discovery is how prolactin is able to get to the DNA of the cell and what it does there. For years, scientists assumed that as a peptide protein, prolactin worked from a distance, outside the cell (unlike steroid hormones which have the ability to leap across the cell membrane on their own, without any help). And indeed, prolactin does work outside the cell. It binds to prolactin receptors, proteins found at the surface of breast cells. When prolactin locks into the receptors, these receptors send out signals that activate genes to stimulate the production of proteins necessary for either milk production in normal breast cells or cancerous growth and spread in malignant ones.

But Dr. Clevenger did not believe this was the only way prolactin worked. Using breast cancer cells in a petri dish, he showed that prolactin is able to physically enter the cell, travel straight to the cell’s DNA, and directly activate the process that turns on genes and triggers the growth of breast cancer cells. It does this by binding to a protein called cyclophilin B, or CYPB for short. This protein serves as the chaperone (a scientific term as well as a very good descriptor) across the cell membrane and into the DNA. CYPB also is an active partner in turning on the genes critical in the development of cancer.

This is exciting news, says Dr. Clevenger. It means we can target drugs to particular tissues in ways not possible before. His own laboratory has applied mutant forms of the CYPB protein to breast cancer cells in vitro and found that breast cancer cells die and normal cells don’t. He says, “When scientists began to understand the implications of the hormone estrogen on breast cancer, it became possible to develop drugs to combat estrogen’s role. When it comes to combating the role of prolactin in breast cancer, we’re 10 years behind where we are with tamoxifen therapy. But then, with advances in science, what once took 10 years may now only take five years.”

The discovery of how prolactin enters the cellular DNA is also exciting because “there is a larger message here than breast cancer,” according to Dr. Clevenger. Other laboratories are finding other peptide hormones that wind up in the nucleus: hormones like epidermal growth factor, growth hormone, insulin. They haven’t yet found the mechanism similar to the chaperone protein that works for prolactin, but Dr. Clevenger hopes his findings will provide new therapies for other malignancies and diseases such as diabetes.