PROJECT DISCRIPTION / ABSTRACT Steroid hormone estrogen, influence development and progression of breast cancer via interactions with estrogen receptor-alpha (ERalpha). At diagnosis, approximately 70% of breast tumors express ERalpha. Therapeutic advances offer various forms of endocrine therapy for patients with estrogen sensitive (ERalpha positive) tumors. However, tumor relapse or therapy resistance is a major clinical problem and breast cancer remains the second most lethal malignant disease for women worldwide. The critical need for more precise diagnostic/prognostic biomarkers and novel targets for endocrine therapy has prompted deeper investigation into the regulation and function of ERalpha pathobiology by coregulatory proteins. ERalpha-coregulator PELP1 mediates both nuclear and extra-nuclear signaling of estrogen as well as facilitates crosstalk between ERalpha and growth factors. Prior in vitro studies suggest PELP1?s tumorigenic potential stems from an ability to assemble and coordinate various signaling pathways with ERalpha. PELP1 deregulation occurs in various endocrine-related cancers, associates with undifferentiated more invasive breast adenocarcinomas and a pre-clinical study of 1,162 breast tumors identified PELP1 overexpression as an independent prognostic biomarker. Emerging evidence implicates a role of PELP1 in mammary tumorigenesis however;the functional role and mechanism of PELP1 action in vivo are unknown. The general hypothesis of my proposal is PELP1 functions as a protooncogene and its deregulation contributes to mammary tumor initiation and progression in vivo. To test the functional role and characterize the molecular mechanism of PELP1 action in vivo, I previously generated an inducible transgenic murine breast cancer model of PELP1 overexpression. To investigate my hypothesis Aim 1, will determine the in vivo significance of deregulated PELP1 expression during the initiation and progression of breast cancer utilizing our novel inducible animal model.
Aim 2 will elucidate the molecular mechanisms by which PELP1 promote mammary tumor initiation.
Aim 3 I will test the therapeutic potential of targeting PELP1-KDM1 axis using FDA approved drug pargyline. Contributions from my proposed studies will not only increase our understanding of ERalpha-mediated tumorigenesis by coregulators but also establish PELP1-axis as a novel candidate for therapeutic intervention. Ultimately, findings from our research have potential to enhancing breast cancer-free survival through advancements and/or creation of new strategies for the next generation in anti-estrogenic therapies for individualized patient care.
Novel targets to enhance endocrine therapy and more precise diagnostic/prognostic biomarkers are critically needed as breast cancer remains the second most lethal malignant disease for women. My proposed research is clinically significant as it will define the role(s) of ERalpha coregulator PELP1 as a critical proto-oncogene of breast cancer initiation and progression. Further, my proposed studies establish the therapeutic potential of PELP1-KDM axis in breast tumorigenesis and thus provide a novel target for combination therapies to treat advanced breast tumors.
|Mann, Monica; Cortez, Valerie; Vadlamudi, Ratna (2013) PELP1 oncogenic functions involve CARM1 regulation. Carcinogenesis 34:1468-75|