Estrogen Receptor Beta Agonists to Prevent Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Peter Kushner, Ph.D. -
Award Cycle: 2005 (Cycle 11) Grant #: 11IB-0028 Award: $150,000
Award Type: IDEA
Research Priorities
Etiology and Prevention>Prevention and Risk Reduction: ending the danger of breast cancer



Initial Award Abstract (2005)
Introduction: The drug tamoxifen has a remarkable ability to block the production of all types of breast cancer when given early in life to rodents. Tamoxifen binds to estrogens receptors (ERs) and slows estrogen-driven proliferation in the mammary gland, a process that eventually results in the occurrence of the gene mutations that underlie cancer. Unfortunately, tamoxifen cannot be given to young women as a chemopreventive because it causes artificial menopause. When taken by older women tamoxifen inhibits formation of estrogen receptor (ER) positive but not the more highly aggressive ER negative breast cancer. New, second generation, drugs that target only one of the two ERs, called ERbeta, block the ability of estrogen to drive cancer-causing cell proliferation without causing artificial menopause. Thus there is reason to think that the ERbeta ligands might be developed into a chemoprevention taken by young women to protect them from all types of breast cancer.

Hypothesis: Our hypothesis is that ERbeta-specific agonists will inhibit estrogen stimulated proliferation in mammary epithelial cells both in cells grown in laboratory culture and in the mammary gland of mice that have been genetically engineered to develop (ER negative) breast cancer. We further hypothesize that by such inhibition of proliferation ER?eta agonists will inhibit the initiation of all breast cancer in those mice.

Methods: We will use two methodologies. Our lab has genetically engineered a commonly used cell line from a human breast cancer called MCF-7 so that it has both ERalpha and ERbeta. We will test the ability of these ERbeta+ cells to grow when exposed to estrogen or estrogen plus a new drug that targets specifically ERbeta called DPN. We will assay cell cycling, doubling time, and cell survival in these cells to see whether DPN blocks proliferation and/or encourages cell death. In a second methodology we will examine the effects of DPN implants to prevent the first stages of breast cancer in mice that have been engineered to develop breast cancer. These MMTV-neu mice first develop nodes of overgrowth in the mammary gland, which after many months become cancerous. In the short time we have for this study we will examine the ability of DPN to prevent the overgrowths. If this project has an encouraging result, we will monitor actual cancer production in a follow up study.

Innovative Elements: The main innovative element in this proposal is the testing of an ERbeta specific agonist for its effects on the processes that lead to breast cancer. A huge literature and experimental effort is directed towards the effects of tamoxifen and other first generation ER ligands on cells in culture, mice, and women. No one has reported, and we believe no one previously has proposed using the new ERbeta specific ligands to prevent breast cancer. Thus our proposal to test such drugs on cells in culture and in mice is entirely novel. In part the suggestion to use these new drugs draws on previous work from our lab showing that ERalpha and ERbeta have opposing effects on the function of genes that direct the cell to proliferate. ERalpha stimulates the function of these genes and ERbeta inhibits them. Because we are acutely aware of this opposition we were eager to test drugs that specifically target ERbeta as soon as chemists developed them.

Advocates: The PI is a an active member of the UCSF Breast Oncology Program in which Advocates play a central role especially evident in our weekly seminar meetings and the discussion that follows. The proposal here was discussed with Peggy Devine our Advocate Coordinator and other advocates and grew essentially out of numerous past conversations with advocates. Many advocates have impressed on the investigator the importance of investigating new strategies to eliminate breast cancer. Above all, I remember an advocate chairman at a session at which I spoke last summer who feared for her 14 year old daughter and the risk of breast cancer. To assuage the mother the daughter told her, “Look mom, I can have a good life even if I get breast cancer. It's OK." "Well", the advocate told us, "it is not OK and it is not OK for a 14 year old to have to think that way. It is vitally important for us to think about ways to prevent breast cancer." It is to this request that this application has responded.


Final Report (2007)
Overall scientific goals: This project aimed to investigate whether ERbeta (ERβ) ligands might be developed into a chemo-prevention taken by young women to protect them from all types of breast cancer. We will here test whether ERβ -specific ligands (either agonists or antagonists) will inhibit estrogen stimulated proliferation in mammary epithelial cells both in cells grown in laboratory culture and in the mammary gland of mice that have been genetically engineered to develop (ER-negative) breast cancer.

As this project developed we chose to focus on the use of a human breast cancer cell line that our lab has genetically engineered so that it has both ER? and ERβ. We tested the ability of these ERβ+ cells to grow when exposed to estrogen or estrogen plus new drug candidates that targets specifically ERβ. We assayed cell cycling, doubling time, and cell survival in these cells to see whether the beta specific ligand blocks proliferation and/or encourages cell death. Although we were originally enthusiastic about a drug called DPN, which is an ERβ-specific agonist because it slightly inhibited the estrogen driven proliferation of the ERβ+ cells, we decided to also investigate alternative ERβ ligands. A German company, Schering AG supplied us with new ERα and ERβ specific ligands that enabled us to alter our aims to include a broader selection of ligands. Because of this expansion of ligands investigated in cell culture we dropped our aims for studies in mice.

The major research milestone of was the discovery of the action of various ligands for ERβ to control the proliferation of human breast cancer cells growing in culture. A second milestone was the discovery of the mechanisms whereby the presence of ERβ greatly increases the responses of breast cancer cells to the anti-estrogen tamoxifen. This latter milestone was recently published in Breast Cancer Research. Our published results indicated that ERβ specifically cooperates with anti-estrogens. The combination of ERβ expression, which arrests cells in G2, and tamoxifen, which arrests cells in G1, led to a potent blockade of the cell cycle. ERβ also increased tamoxifen-induced cell death and cooperated with tamoxifen to induce expression of the pro-apoptotic gene bik. In summary, our data indicates that ERβ increases the efficacy of anti-estrogens by effects on apoptosis and on cell cycling and, together with clinical observations, suggests ERβ could be a valuable prognostic marker and potential therapeutic target.

Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells.
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Hodges-Gallagher L, Valentine CD, Bader SE, Kushner PJ
Yr: 2007 Vol: Epub Nbr: Abs: Pg:PMID: 17638070