Unique estrogen receptor linked to metastatic breast cancer

November 01, 2006

Providence, RI ¡V Breast cancer awareness month may have passed, but researchers remain focused on the disease with a new study showing that a unique estrogen receptor found in breast cancer tumors is a predictor of tumor size and metastases. The study, led by researchers at Rhode Island Hospital and Brown Medical School, is published in the November 1 issue of Clinical Cancer Research.

"We found that a novel estrogen receptor, termed GPR30, is linked to breast tumor progression and increased tumor size,"says lead author Edward J. Filardo, PhD, research associate at Rhode Island Hospital and assistant professor at Brown Medical School. "Furthermore, the results support prior research suggesting that GPR30 acts independently from the two known estrogen receptors, ERƒÑ and ERƒÒ."

Estrogen receptors act like ears on a breast cancer cell ¡V estrogen attaches to the receptor and transmits signals that tells the cell to grow and multiply. Physicians test for receptors to help determine the most appropriate treatment for breast cancer patients. Typically, the more estrogen receptors present, the more likely the patient will respond to hormone therapy, such as tamoxifen.

However, approximately one in four patients that test positive for estrogen receptors, do not respond to hormone therapy prompting scientists to propose that there may be additional types of estrogen receptors that play a role tumor growth. Filardo and co-author Jeffrey Quinn, PhD, first identified GPR30 as a potential alternate estrogen receptor capable of triggering breast cancer cell growth in 2000.

In an effort to further refine the classification of GPR30, researchers in this study analyzed 361 tumor samples from breast cancer patients to compare the distribution patterns of standard estrogen receptors (ER) and GPR30. They examined how the various estrogen receptors associated with each other and their relationship with size of the primary breast tumor, lymph node invasion, and development of metastasis.

Results showed that while the two types of receptors, GPR30 and the standard ERs, were commonly found together - their expression was not interdependent. This was best evidenced by the fact that approximately half of the ER-negative tumors remained positive for GPR30.

"This suggests that tumors traditionally viewed as being unreceptive to estrogen, may in fact, remain estrogen responsive," says co-author Edmond Sabo, MD, pathologist at Rhode Island Hospital and assistant professor at Brown Medical School. "If this is the case, it could significantly influence which patients are candidates for hormone therapy."

Researchers also found that GPR30 was positively associated with tumor size, and that primary tumors from patients with metastatic disease were twice as likely to express GPR30.

Alternatively, an inverse relationship was measured between the standard estrogen receptors (ERƒÑ and ERƒÒ) and tumor size, and no significant association was found between receptor expression and the presence of metastatic disease.

"Our data indicates that GPR30 promotes tumor growth and is linked to metastatic disease, but also evidences GPR30's autonomy from the standard estrogen receptors," says Filardo. " It strengthens the concept that GPR30 and standard estrogen receptors promote distinct biological responses and invokes a new paradigm regarding our current understanding of breast cancer biology."

Interestingly, although GPR30 was strongly associated with the development of metastatic disease, there was not a connection between the presence of GPR30 and if breast cancer cells had invaded the lymph nodes of a patient.

"Further research is needed to determine if there is a relationship between GPR30 and lymph node invasion," says Filardo. "Given that tumor size and lymph node invasion are well-known predictors of metastases, future studies will focus on determining how cells that test positive for GPR30 spread throughout the body."
The research team also includes Carl Graeber, Murray Resnick, MD, Dilip Giri, MD, Ronald DeLellis, MD, Rhode Island Hospital and Brown Medical School; and Margaret Steinhoff, MD, Women and Infants Hospital and Brown Medical School. The National Center for Research Resources, a component of the National Institutes of Health, funded the work.

Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of Brown Medical School. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks 13th among independent hospitals who receive funding from the National Institutes of Health, with research awards of more than $27 million annually. Many of its physicians are recognized as leaders in their respective fields of cancer, cardiology, diabetes, orthopedics and minimally invasive surgery. The hospital's pediatrics division, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery. Rhode Island Hospital is a founding member of the Lifespan health system.


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