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Role of Estrogen Receptor Beta in Response to Tamoxifen Therapy
Currently, ERalpha presence is the only basis for treating breast cancer patients with tamoxifen therapy. Based on the presence of ERalpha alone the response rate with tamoxifen is 50%. It is now well established that breast cancer tissues express a second structurally related but genetically distinct ERbeta , which modulates ERalpha in addition to being an independent mediator of estrogen signaling. It is not known how the presence of ERbeta influences the disease free survival to tamoxifen therapy. Our long range goal is to understand how the expression levels of ERbeta and its two isoforms, ERbeta2 and ERbeta5, that also modulate ERalpha, influence the disease free survival following above therapy. The objective of this application is to determine whether the five year relapse free survival to tamoxifen therapy could be better predicted if relative levels of ERbeta1, ERbeta2 and ERbeta5 to ERalpha are taken into consideration instead of ERalpha alone. The central hypothesis of the application is that the relative levels of each ER influence the disease free survival following tamoxifen therapy. The hypothesis has been formulated based on strong preliminary data, which suggested that although ERalpha was a good predictor of sensitivity (5 year relapse free survival), it was a poor predictor of specificity (relapsed in 5 years) to tamoxifen therapy. The specificity was enormously improved when the relative levels of the three ERbeta isoforms plus another isoform of ERalpha, exon 5delta, to the wild type ERalpha levels, were taken into consideration. The rationale for the proposed research is that once it is known how ERbetas could improve the specificity, that information could be used to identify a sub-group of ERalpha+ patients who will relapse in five yeas following tamoxifen treatment. The central hypothesis will be tested and the objective of the application accomplished in a retrospective study to establish a ‘Proof of Principal’ that ERbeta isoforms play a role in response to tamoxifen therapy, by pursuing two specific aims : 1 ) Identify the ERbeta isoform(s) which in combination with ERalpha, correlates with five year relapse/disease free survival to tamoxifen, 2) Establish the ratios of ER isoform mRNA copy numbers that correlate with five year disease/relapse free survival to tamoxifen. It is our expectation that we will identify a combination of ER isoforms that are better predictors of five year disease free survival to tamoxifen therapy.
Tamoxifen has been the major therapy for patients who express estrogen receptor (ER or ERalpha) in their tumors. It has saved millions of lives through out the world. However not every ERalpha-positive patient responds to this therapy. Several clinical studies have shown that about 50% of ERalpha-positive patients do not respond to this therapy. It is not known what causes half the people to not respond to tamoxifen therapy. Several laboratory studies have suggested that tumor tissues have another marker called ERbeta that is closely related to ERalpha that could influence the outcome with tamoxifen therapy. However, the role of ERbeta in tamoxifen therapy has not been established until now because of the unavailability of methods to quantify these two receptors in tumor tissues. We investigated whether ERbeta influences response in a limited number of cases by using state-of-the-art methods developed in our laboratory that could precisely quantify the levels of not only ERbeta but also ERalpha. We defined the response as five year disease free survival after diagnosis and initiation of tamoxifen therapy. Our preliminary results suggested that ERbeta to ERalpha ratio is higher in patients who show five year relapse free survival compared to those who relapsed. Here, we submit a plan to “establish a proof of principle” that ERbeta influences the response by conducting a retrospective study. We will quantify the ERalpha and ERbeta in tumors, review the charts of patients from whom we have obtained the tumors for relapse free years and establish a correlation between the ratios of these two receptors with relapse free survival years. We are well prepared to conduct this study because we have over 250 fresh frozen tissues stored in our laboratory which were collected over a period of nine years, we are the first and the only group who have developed methods to quantify ERalpha and ERbeta in tumor tissues. In addition, we have the participation of a breast pathologist, oncologist to review patient charts about five year disease free survival and statisticians to assist us in our studies. It is our expectation that we will establish that by taking the combination of ERbeta and ERalpha will better predict the likelihood of five year disease free survival to tamoxifen therapy. Such outcomes will be significant , because it is expected that the new knowledge will suggest alternate therapies for patients who are likely to relapse to these therapies.