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Restoring ER Expression and Anti-Estrogen Response to ER-Negative Breast Cancers
Tumor Cell Biology II
Loss of estrogen receptor (ER) in breast cancer correlates with a more aggressive, tamoxifen resistant phenotype. ER negative tumors often display overexpression or amplification of growth factor receptors of the erbB family, particularly EGFR and erbB-2, and consequently have elevated growth factor signaling and resultant MAP kinase (ERK) activity. We have previously shown that overexpression of these EGFR or erbB-2, or constitutive activation of Raf or MEK in ER+, estrogen-dependent MCF-7 cells results in the loss of ER expression and acquisition of estrogen independence. We have also shown that the common downstream effector of ER downregulation in all our model cell lines is hyperactive MAPK. Importantly, inhibition of MAPK activity in our cell lines and other breast cancer cell lines restores ER expression, and treatment of breast tumor specimens ex vivo with a MEK inhibitor results in re-expression of ER mRNA. The three specific aims of this proposal are designed to determine if the reversal of this ER-negative phenotype can be extended to clinical breast tumor specimens and, importantly for clinical development, results in the restoration of tamoxifen-sensitivity in vivo . They will test the hypotheses that there exists a subpopulation of ER- tumors in which ER expression and anti-estrogen response can be restored. Specifically, we will: 1) determine whether the increased ER mRNA observed upon treatment of tumor specimens correlates with increased ER protein in tumor cells; 2) determine the mechanisms underlying lack of restoration in those tumors that do not re-express ER, ; and 3) using both in vitro and in vivo models, determine if the re-expressed ER results in restoration of estrogen dependence and anti-estrogen sensitivity.
The overall goal of this project is to develop a novel therapeutic strategy for the treatment of estrogen receptor (ER) negative breast cancer. The presence of ER in a breast tumor is important as it is the key determinant of whether a patient's tumor will respond to hormonal therapies like tamoxifen. The estrogen receptor (ER) is the protein that binds estrogen and mediates its action as well as the protein that binds tamoxifen and mediates its action. If a breast tumor lacks ER, that is ER-negative, it will not respond to anti-hormonal therapies and patients with such tumors are relegated to more toxic chemotherapies. ER- tumors tend to overexpress growth factor receptors such as the epidermal growth factor receptor (EGFR) or c-erbB-2 (also known as Her-2). We have previously demonstrated using breast cancer cell line models that such EGFR or c-erbB-2 overexpression directly causes the ER- phenotype by down-regulating the expression of ER. We have determined that it is the resultant hyperactivation of MAPK downstream of overexpressed EGFR or c-erbB-2 that downregulates ER expression and have established the key mechanisms underlying this phenomenon. We now want to develop this basic science work into a clinical approach to treat ER- breast cancer. Based on preliminary data indicating that we can restore ER expression to ER- breast cancer cell lines, that this re-expressed ER is functional in respect to mediating an anti-estrogen response, and that we can restore ER mRNA expression in breast tumor specimens, we propose to establish that these mechanisms are operative in vivo. That is, using in vivo models of ER- breast cancer, we will establish that inhibition of MAPK activity will restore both ER expression and anti-estrogen response. We will also determine whether the increased ER mRNA that occurs in breast tumor specimens upon inhibition of MAPK correlates with increased ER protein expression specifically in the tumor cells. And finally, we will determine the mechanism behind a lack of restoration of ER expression upon MAPK inhibition in those tumors that do not respond. It is our hypothesis that there exists a population of ER- breast tumors in which ER expression is being suppressed by the signaling of the overexpressed EGFR or c-erbB-2. We propose that, in these tumors, it will be possible to not only restore ER expression but more importantly, restore anti-estrogen response. The successful completion of the work proposed here would lead directly to a clinical trial testing the efficacy of combined MAPK inhibition and anti-estrogen therapy in ER- breast cancers.