Scientists report marker of increased cancer risk in women with benign breast disease

December 14, 1999

NASHVILLE, Tenn. - Women with a benign breast disease whose cells lose the ability "to hear" signals instructing them not to divide are at increased risk of later developing breast cancer, Vanderbilt-Ingram Cancer Center researchers have found.

In the Dec. 15 issue of the Journal of the National Cancer Institute, the scientists report that a reduction in expression of a receptor for transforming growth factor beta (TGFb) occurs early in the progression from hyperplasia to malignancy in some women. Hyperplasia is a benign condition that involves an overgrowth of apparently normal cells.

"This is the first time we've found credible evidence of a biologic marker of increased breast cancer risk in women with unequivocally benign breast disease," said William Dupont, Ph.D., professor of Preventive Medicine at Vanderbilt.

A laboratory test to determine levels of expression of this receptor might be used in the future to reassure women at no increased risk or to guide decisions about screening and preventive measures in women whose risk is elevated, Dupont said. In addition, the findings suggest a new angle for scientists to explore in developing prevention strategies.

TGFb is a powerful regulator of cell growth whose job is to instruct cells not to divide. The cells "hear" this signal through the TGFb type II receptor, into which TGFb locks itself before sending its instructions to the cell nucleus.

This research builds on more than two decades of work by Dupont, Dr. David Page, and their colleagues with a group of nearly 10,000 women who underwent biopsies revealing benign breast disease at three Nashville hospitals over a 30-year period. Through their ongoing analysis and follow-up of the Nashville Breast Study Cohort - the largest of its kind - this research team has contributed greatly to the understanding and definition of benign breast disease.

"We have found that there are different types of benign breast disease with different levels of risk," Dupont said. "Most women who have undergone benign breast biopsy - about 70 percent - have non-proliferative disease that's not associated with any elevation in risk. A minority, about 4 percent, have a four- to five-fold increase in risk, while the remainder have only a mild elevation of risk."

Thus far, indicators of breast cancer risk identified through this work have been based on histology - how the cells look under the microscope in terms of shape, size, distribution and so forth. A few so-called molecular markers - abnormal expression of particular cancer-related genes like p53 or HER-2/neu, for example - have been identified that help predict prognosis in patients with well-established breast disease. This latest work focuses on differences in risk among women with the same diagnosis of benign breast disease based on histology.

"Finding molecular markers of risk in women who are still very far away from developing breast cancer has been difficult," Dupont said. "Breast cancer is a disease with a very long memory. Things that happen during a woman's second decade of life - age of first menstruation, age of first pregnancy - can affect a woman's risk of developing breast cancer decades later. There are things happening in the cell over a long period of time and it would nice to know what they are."

The scientists identified 54 women in this cohort whose biopsies, conducted between 1965-1978, revealed a diagnosis of epithelial hyperplasia lacking atypia and who subsequently developed invasive breast cancer. Each was matched to two "control" women with the same diagnosis, of similar age and whose diagnostic biopsy was done at about the same time. However, the women in the control group did not develop breast cancer during subsequent follow-up.

The researchers tested tissue removed at the time of each woman's initial biopsy with antibodies to the TGFb type II receptor. This test produces a brown stain in cells in which this receptor is active (expressed).

By analyzing expression of the TGFb receptor and subsequent development of invasive breast cancer, the researchers discovered that the fewer the cells able "to hear" TGFb's signals, the greater the cancer risk. Specifically, when the receptor was expressed in fewer than 25 percent of the cells, the woman had more than three times the risk of subsequent invasive breast cancer, compared to women who had receptor expression in greater than 75 percent of their cells.

The findings "make sense" given what scientists know about TGFb's function, Dupont said. "This also is exciting because ordinary hyperplasia is a common condition," he said. "This will help to subdivide between those who have no reason for increased concern and those who may have a moderate elevation in risk," he said. "For these women, having regular mammograms might go from being a good idea to being a very good idea, and it might lower the age at which they might want to start. It adds another piece of information for women, physicians and genetic risk counselors to consider."

The work was supported by the National Cancer Institute and the Vanderbilt-Ingram Cancer Center. Dupont's colleagues include Dr. Helenice Gobbi, pathology fellow and first author on the JNCI paper; Dr. Jean Simpson, associate professor of Pathology and director of Anatomical Pathology; systems analyst W. Dale Plummer Jr.; research nurse Peggy Schuyler; Sandra Olsen, research instructor in Pathology; Dr. Carlos Arteaga, Ingram Professor of Cancer Research; and Page, professor of Pathology and Preventive Medicine.
As one of a select group of National Cancer Institute-designated cancer centers, the VICC is a recognized leader in cancer research, treatment and prevention. The VICC is one of only a few NCI-designated centers in the southeast and the only one in Tennessee dedicated to providing the most promising therapies and advancing research in all cancers in adults and children. For more information, visit .

Vanderbilt University Medical Center

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