Riggins Lab:Notebook/Susan G. Komen Project
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The reasons for this discrepancy are almost entirely unknown, and unfortunately the current laboratory models that are used to study antiestrogen resistance have all been derived from ductal carcinomas. To address this deficiency, we have developed a breast cancer cell culture model of invasive lobular carcinoma that has become resistant to the antiestrogen Tamoxifen. In this model we have found that increased expression of the gene estrogen related receptor gamma (ERRγ) plays an essential role in Tamoxifen resistance, and that its function is likely to be modified or changed by the activity of a second gene, extracellular signal-regulated kinase (ERK). When we examined ERRγ in breast tumors, we observed that levels of the ERRγ gene are significantly higher in the tumors of breast cancer patients who relapsed following Tamoxifen therapy as compared to those women who did not experience recurrence. Importantly, in this study the association of ERRγ with Tamoxifen resistance was not restricted to women with ILC, which suggests to us that ERRγ may be a biomarker for poor response to Tamoxifen in many different types of breast cancer.
The idea we will be testing is that ERK regulates ERRγ’s function in TAM-resistant breast cancer. In Specific Aim 1, we will use our new cell culture model of invasive lobular carcinoma to understand how ERK regulates or modifies ERRγ function and whether this explains how these breast cancer cells have become resistant to Tamoxifen. In Specific Aim 2 we will look more closely at ERRγ expression in breast tumor specimens from 150 patients with ductal and lobular breast cancer in order to determine whether high expression of this gene is linked to poor overall survival, poor response to Tamoxifen, and the activity of ERK.
Our innovative studies will advance our understanding of how and why ERRγ regulates resistance to antiestrogens in breast cancer. These are important clinical problems, and furthering our knowledge in these areas will make a significant impact on breast cancer research as a whole. In the near-term, we anticipate that our findings will specifically benefit the ~128,000 women who develop ER+ breast cancer each year by identifying ERRγ as a new biomarker for poor response to Tamoxifen. This would allow clinicians and patients to choose a more appropriate therapeutic regimen that will improve overall survival and disease outcome. Given the recent successes of ERK pathway-specific inhibitors in phase I and II clinical studies we believe that co-measurement of ERRγ and active ERK in breast tumors might also serve as a rationale for targeted, combination therapy of endocrine agents and ERK inhibitors. Finally, our results will also impact the long-term future of breast cancer research and treatment by helping clinicians and researchers to better understand the molecular biology of the ILC subtype, which is increasingly diagnosed yet poorly understood.