Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract
    Awarded Grants
    Designer Transcription Repressors: Toward the Treatment of Endocrine Resistant Breast Cancers

    Scientific Abstract:
    Although many factors contribute to breast cancer etiology, estrogen hormones, particularly 17-b estradiol (E2), play critical roles in the initiation and development of the disease. The effects of E2 are mediated by the estrogen receptors (ERs) a and b. E2-ER regulates genomic and non-genomic events involved in cell proliferation, differentiation and death. The current modalities for the treatment of breast cancer utilize agents to reduce/ablate the circulating E2 or to alter/prevent ER function. Approaches to perturb the E2/ER environment promote initial remission of tumors. However, many breast cancers eventually develop resistance to such therapies. This fact necessitates the development of new therapeutic approaches to combat the disease. The interaction of E2-ER with specific DNA sequences, estrogen responsive elements (EREs), is a major signaling pathway. We hypothesized that specific targeting and potent repression of ERE-driven genes would provide a sufficient and necessary basis for the treatment of endocrine sensitive and resistant breast neoplasms. To test this postulate, we engineered novel transcription repressors that specifically and potently suppress ERE-driven transcription independent of ligand, ER-subtype or –status or of other E2/ER signaling pathways. Importantly, these repressors suppressed cell cycle progression in cells, emphasizing the pivotal importance of the ERE-driven gene network in cell proliferation. We therefore predict that specific repression of ERE-containing genes would also suffice to alter phenotypic characteristics of model endocrine resistant cells thereby providing a basis for the development of a therapeutic approach. We propose to assess alterations in cell proliferation, invasiveness and apoptosis in response to designer repressors delivered by recombinant adenovirus in model cells that emulate endocrine sensitive and resistant breast cancers. We also aim to identify ERE-driven genes using gene array approaches to understand how genomic responses correlate with the manifestation of cell phenotypes. This discovery could be critical for the identification of new therapeutic targets, the development of prognostic tools and of modalities for prevention and treatment of breast cancer.

    Lay Abstract:
    The development of breast cancer is the consequence of uncontrolled growth and division of breast-ductal epithelial cells. While many factors contribute to the etiology of breast cancer, estrogen hormones, particularly 17-b estradiol (E2), are critical agents for the initiation and development of this disease. The effects of E2 are mediated by transcription factors, estrogen receptor (ER) a and b. Current clinical approaches using endocrine treatments to perturb the E2/ER environment of the tumor cells are often successful in the remission of established tumors. However, the beneficial effects of these endocrine measures, particularly antiestrogen treatments, are counteracted by the capacity of the tumor cells to eventually circumvent such therapies, allowing the cells to continue to grow and progress (endocrine resistance). The interaction of E2-ER with specific DNA sequences, called estrogen responsive elements (EREs), is a major signaling pathway. We postulated that specific targeting and potent repression of ERE-driven genes would provide a basis for the treatment of endocrine resistant breast neoplasms. To test this prediction, we engineered novel proteins that specifically and potently suppress ERE-driven genes, thereby halting cell proliferation. Based on these observations, we hypothesize that specific repression of ERE containing genes would also suffice to repress cancer phenotypes of model endocrine resistant cells. This could provide a basis for the development of a novel therapeutic modality. To further assess the effectiveness of our approach, we propose to investigate alterations in endocrine sensitive and resistant cell phenotypes such as cell proliferation, invasiveness and survival in response to our designer transcription repressors. We also propose to identify ERE-driven genes using gene array approaches to understand how genomic responses correlate with the manifestation of cell phenotypes. This discovery could be critical for the identification of new therapeutic targets, the development of new prognostic tools and the promotion of new modalities for prevention and treatment of breast cancer.