Public Release: 

Newly discovered mutations possibly linked to breast cancer

University of Illinois at Chicago

In a study published this week in the New England Journal of Medicine, a researcher at the University of Illinois at Chicago has identified two previously unknown mutations that cause excessive estrogen production in men -- and may be linked to certain kinds of breast cancer.

"These mutations may be a subset of genes responsible for inheritable breast cancers that depend on estrogen for their growth," said Dr. Serdar Bulun, director of reproductive endocrinology and infertility at the UIC College of Medicine and a member of the UIC Cancer Center.

Bulun discovered the mutations when investigating the cases of three male patients who had been referred to him. All three -- a man and his son, and an unrelated individual -- suffered from severe gynecomastia, a disorder characterized by enlarged breast tissue in males. Previous investigations by other doctors had shown no apparent cause, such as an estrogen-producing tumor.

In a meticulous series of experiments, Bulun and his colleagues found that the individuals had abnormally high levels of estrogen, a hormone associated with the female reproductive function but also present in small quantities in men.

In skin, fat and blood samples taken from the three males, estrogen levels were found to be up to 24 times the normal level.

Bulun's laboratory discovered that two similar genetic defects -- one in the father and son, and one in the other individual -- were the cause of the excessive hormone production.

Both defects were located on chromosome 15, where the gene for aromatase, an enzyme that synthesizes estrogen, resides, Bulun said.

The defects involved the misplacement of promoters associated with "housekeeping" genes, which manufacture everyday necessities to keep the body functioning, such as basic proteins that form the building blocks of cells.

Promoters are segments of DNA that mark the starting point for transcription, or expression, of a gene. These particular promoters are configured to ensure that the housekeeping genes produce large amounts of the needed proteins around the clock.

Because of the genetic mutations, however, the promoters of the housekeeping genes in these three patients were accidentally placed in front of the gene for aromatase, encouraging continuous production of the enzyme -- and elevated levels of estrogen.

Bulun and his colleagues were able to show that the defects must have occurred when the individuals' chromosomes duplicated during cell division, perhaps as the embryo was developing.

When the two strands of DNA replicated and then split apart, separating into each of the two daughter cells, one strip of DNA -- the piece containing the promoter -- separated and flipped over, ending up linked to the opposite strand and repositioned next to the aromatase gene. The boy suffering from gynecomastia likely inherited the mutation from his father.

"Occasional mutations such as these cause extraordinarily increased estrogen production and striking clinical consequences," Bulun said. "More common mutations may go clinically unrecognized and cause subtle degrees of estrogen excess, increasing the risk of estrogen-dependent disease, such as breast and endometrial cancer and endometriosis."


Other researchers involved in the study were Makio Shozu at UIC and Kanazawa University in Japan, Siby Sebastian at UIC, Kazuto Takayama at Tohoku University in Japan, Wei-Tong Hsu at Rush Medical School in Chicago, Roger Schultz at the University of Texas Southwestern Medical Center at Dallas, Kirk Neely at Stanford University, and Michael Bryant at Children's Hospital in Los Angeles.

For more information about the UIC College of Medicine, visit

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