A Third (and New) Estrogen Receptor Is Discovered And Is Directly Tied To

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METASTASIS...IT MAY ALLOW SO CALLED ER- TUMORS TO BENEFIT FROM ANTIESTROGEN THERAPY!

POSTED HERE AS DESERVES WIDE READERSHIP!

Unique Estrogen Receptor Linked to Metastatic Breast Cancer [Lifespan]
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, ERa and ERb."

Estrogen receptors act like ears on a breast cancer cell—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 estrogen receptor capable of triggering breast cancer cell growth in 2000.

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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 (ERa and ERb) and tumor size, and no significant association was found between receptor expression and the presence of metastatic disease.

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"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."

The authors note 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.

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ABSTRACT: Distribution of GPR30, a Seven Membrane.Spanning Estrogen Receptor, in Primary Breast Cancer and its Association with Clinicopathologic Determinants of Tumor Progression [Clinical Cancer Research]
Purpose: The seven transmembrane receptor, GPR30, is linked to estrogen binding and heparan-bound epidermal growth factor release. Here, the significance of GPR30 in human breast cancer was evaluated by comparing its relationship to steroid hormone receptor expression and tumor progression variables.

Experimental Design: Immunohistochemical analysis of a National Cancer Institute-sponsored tumor collection comprised of 361 breast carcinomas obtained at first diagnosis (321 invasive and 40 intraductal tumors). Biopsies from 12 reduction mammoplasties served as controls. The distribution pattern of GPR30, estrogen receptor (ER), and progesterone receptor (PR) was correlated with clinicopathologic variables obtained at diagnosis.

Results: GPR30, ER, and PR were positive in all 12 normal controls. In contrast, GPR30 expression varied in breast tumors, in which 62% (199 of 321) of invasive tumors and 42% (17 of 40) of intraductal tumors were positive. Codistribution of ER and GPR30 was measured in 43% (139 of 321) of invasive breast tumors, whereas both receptors were lacking (ER-GPR30-) in 19% (61 of 321) of the tumors analyzed, indicating a significant association between ER and GPR30 (P < 0.05). The coexpression of PR and ER did not influence GPR30 expression, yet coexpression of GPR30 and ER was linked to PR positivity. Unlike ER, which varied inversely with HER-2/neu and tumor size, GPR30 positively associated with HER-2/neu and tumor size. In addition, GPR30 showed a positive association with metastasis (P = 0.014; odds ratio, 1.9).

Conclusions: GPR30 and ER exhibited distinct patterns of association with breast tumor progression variables, including HER-2/neu, tumor size, and metastatic disease. Thus, these results support the hypothesis that GPR30 and ER have an independent influence on estrogen responsiveness in breast carcinoma.

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in this article from 2005: http://www.ncrr.nih.gov/newspub/nov05rpt/stories2.asp

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