Newly discovered mutations possibly linked to breast cancer

May 07, 2003

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

University of Illinois at Chicago

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.

Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.

More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.

Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.

Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to