Researchers at Ohio University and New York University Medical Center studied the relationship between growth hormone and the development of ducts and terminal end buds in the mammary gland. Earlier research suggests increased numbers of terminal end buds -- which contain the most rapidly dividing cells in the mammary gland -- may be tied to an increased risk in breast cancer in mice.
In a study presented June 11 in Minneapolis at the 79th Annual Meeting of the Endocrine Society, researchers reported that when they compared the number of terminal end buds in mice genetically engineered to produce a growth hormone antagonist with mice producing normal to high levels of growth hormone, they found that the growth hormone antagonist transgenic mice had fewer terminal end buds. They also found that development of a ductal network that ordinarily appears in the mammary gland prior to puberty was impaired.
"This is the first animal model to allow study of that early phase of mammary development," said David L. Kleinberg, professor of medicine at New York University Medical Center and lead researcher on the project.
Kleinberg's earlier research had shown that the development of terminal end buds at puberty is under the control of growth hormone in conjunction with estrogen, which prompted this new study in the growth hormone antagonist transgenic mice.
"Growth hormone has been implicated in many forms of cancer, including breast cancer," said John Kopchick, Goll-Ohio Professor of molecular biology at Ohio University and inventor of growth hormone antagonist and the transgenic mice used in the study. "Our collaborators at New York University Medical Center have found that inhibiting growth hormone via our growth hormone antagonist has a dramatic effect on very early terminal end bud and duct development. This strongly suggests growth hormone is involved in mammary development at an earlier stage than previously thought."
A better understanding of mammary gland development is needed before the link between terminal end buds and cancer can be confirmed, Kleinberg said.
"If we can understand the control of normal mammary growth and development we might be able to come up with some novel treatments for breast cancer by trying to inhibit the different hormones that affect cell growth," Kleinberg said.
For the study, researchers evaluated mammary growth in groups of growth hormone antagonist transgenic and nontransgenic mice at 32 days old, 55 days old and 90 days old. In the growth hormone antagonist transgenic mice, the number of terminal end buds was significantly lower at all stages of development than the nontransgenic mice in the control group.
But even more interesting, Kleinberg said, was that despite the diminished overall size of the growth hormone antagonist mice and the significantly reduced number of terminal end buds and ducts, their mammary glands were the same size as the mice without growth hormone antagonist.
"We were surprised to find that there was no mammary ductal development in the pre-pubertal stage, and yet the mammary glands were about the same size as those in the control group," Kleinberg said. "This suggests that even with inhibited growth hormone, the overall size of the gland, which is made up mostly of connective tissue, was not abnormal."
The mice used in the study, invented by Kopchick at Ohio University in the late 1980s, contain a unique DNA sequence for growth hormone. Human and animal growth hormone contains a chain of 191 amino acids. Kopchick's research team discovered that by replacing the amino acid glycine -- number 119 in the chain in animals and 120 in humans -- with almost any other amino acid, the growth hormone turns from a growth hormone agonist, or enhancer, to a growth hormone antagonist, or inhibitor.
The university received a U.S. patent on the technology in 1994. Sensus Drug Development Corp. in Austin, Texas, holds the license for the invention and currently is using the technology to develop drugs for human diseases in which growth hormone is elevated, or diseases in which growth hormone has been implicated.
The research was supported by the Veterans Administration Merit Review, the National Institutes of Health, the State of Ohio's Eminent Scholar Program, the Ohio Department of Development Thomas Edison Program and Sensus Drug Development Corp.
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