The Role of a Novel Estrogen Receptor in Breast Cancer

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Ruth Lupu, Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3IB-0118 Award: $231,039
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1997)
One of the major challenges facing breast cancer research today is developing and testing more effective chemoprevention systems, mainly through pharmacological means. Tamoxifen (Tam), a synthetic anti-estrogen, is widely used for the treatment of breast cancer. The administration of Tam to patients with node negative breast cancer induces substantial regression of the tumor and an increase in disease-free survival. The use of Tam was initially restricted to women with estrogen-receptor (ER)-positive tumors. For a number of years, it has been postulated that estrogen and anti-estrogens may have biological effects that are independent of the estrogen receptor.

About 50% of post-menopausal breast cancer patients who are ER-positive (ER+) benefit from anti-estrogen therapy. However, several aspects of this hormonal therapy are still puzzling. There are a large number of ER+ breast cancer patients who do not respond to anti-estrogens. Many patients who initially respond to anti-estrogen therapies eventually acquire anti-estrogen resistance, despite retention of the ER in many of the tumor cells. There are a large number of ER-negative patients who benefit from anti-estrogen treatments. Thus, the simple presence of the classical ER status is insufficient to recommend anti-estrogen treatment and the simple absence of the classical ER is not sufficient to recommend against anti-estrogen therapy. One current working hypothesis is that the expression of ER variants, which are incomplete ER molecules, can suppress the normal function of the ER. This hypothesis has yet to be proven.

Another exciting hypothesis has very recently emerged that may explain the apparently anomalous behavior of some breast cancer tumors with regards to their response to anti-estrogen treatments. A new ER coded by an entirely different gene than the classical ER, has recently been identified. This new ER is now termed ER-b. We have shown that this ER- b is expressed in normal breast and tumor tissue, and it is up-regulated after 48 hours of estrogen treatment. We hypothesize that this new ER- b is a player in suppression or induction of the normal ER- a function. The proposed studies should provide valuable information regarding the role of ER- b, help predict the tumor response to anti-estrogen therapy, and identify those patients that are likely to benefit from anti-estrogen treatment.


Final Report (1999)
One of the major challenges facing breast cancer research today is developing and testing more effective chemoprevention systems, mainly through pharmacological means. Tamoxifen (Tam), a synthetic antiestrogen, is widely used for the treatment of breast cancer. The administration of Tam to patients with node negative breast cancer induces a substantial regression of the tumor and an increase in disease-free survival. The use of Tam was initially restricted to women with estrogen-receptor (ER)-positive tumors. For a number of years, it has been postulated that estrogen and anti-estrogens may have biological effects that are independent of the estrogen receptor.

About 50% of post-menopausal breast cancer patients who are ER-positive (ER+) benefit from antiestrogen therapy. However, several aspects of this hormonal therapy are still puzzling. There are many patients with ER+ tumors that do not respond to anti-estrogens. Many tumors that initially respond to anti-estrogen therapies eventually acquire anti-estrogen resistance, despite retention of the ER in many of the tumor cells. There are many patients with ER-negative tumors who benefit from antiestrogen treatments. Thus, the simple presence of the classical ER status is insufficient to recommend anti-estrogen treatment and the simple absence of the classical ER is not sufficient to recommend against anti-estrogen therapy. One current working hypothesis is that the expression of ER variants, which are incomplete ER molecules, can suppress the normal function of the ER.

We proposed experiments to address this hypothesis. Our aims were: 1) To generate anti-ER beta (ERb) antibodies and to evaluate ERb expression in breast cancer tumors, 2) To study the agonistic or antagonistic consequences of ERb expression on normal and breast cancer tumor cell lines by introducing the full length ERb cDNA, and 3) To define the ability of ERb to pair with another ERb molecule (form homodimers) or pair with an ERa molecule (form heterodimers) in response to estrogen and anti-estrogen.

During the funding period we have 1) generated and tested the specificity of a number of anti- ERb antibodies, 2) we have put ERb into a variety of breast cancer cells and characterized these biochemically and biologically, and 3) we have made all the constructs necessary to address dimerization of the two different ER's. We anticipate that our findings will provide clues to the anomalous breast cancer cases which fail to respond to anti-estrogen therapies and will help assessing which patients should be given this therapy.

Expression of estrogen receptor beta messenger RNA variant in breast cancer.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Vladusic EA, Hornby AE, Guerra-Vladusic FK, and Lupu R
Yr: 1998 Vol: 58 Nbr: Abs: Pg:210-214

Expression and Regulation of Estrogen Receptor beta in Human Tumors and Cell Lines.
Periodical:Oncology Reports
Index Medicus: Oncol Rep
Authors: Vladusic E.A., Hornby A.E., Guerra-Vladsic F.K., Lakins J., and Lupu R.
Yr: 2000 Vol: 7 Nbr: 1 Abs: Pg:157-167