PROJECT SUMMARY / ABSTRACT Breast cancer is the second leading cause of cancer-related deaths in women. Over two-thirds of all breast cancer cases are considered estrogen receptor positive (ER+). Significantly, ER+ breast cancer incidence correlates strongly with aging, rising to a peak incidence in women aged 70 years or older (elderly). Owing in large part to the differences in physiologic estrogen signaling and the chronic inflammatory state that develops as people age, ER+ breast cancer that develops in the elderly population exhibits distinct clinical and biologically behavior from ER+ breast cancer in younger cohorts. Clinically, while endocrine therapy continues to be a mainstay of treatment, there is a major push for de-implementation of invasive and adverse effect- causing interventions in the elderly that do not impact disease-specific survival. Our group has recently shown that in elderly patients with early stage ER+, clinically node-negative tumors, de-implementation of both sentinel lymph node biopsy and radiation therapy can be safely omitted without compromising local recurrence-free or disease-free survival. Biologically, intrinsic epigenomic and transcriptomic as well as changes to local breast microenvironment all contribute to a unique landscape for tumor pathogenesis in aged individuals. The interplay and disease-causing roles of these factors requires further investigation. We will investigate several key questions in this translational proposal: (1) What factors that arise in the backdrop of age-induced chronic inflammation may contribute to distinct tumor signaling in aged ER+ breast tumors? Using patient tumor and plasma samples, we will characterize cytokines, chemokines, and estrogen profiles, connecting these extrinsic factors with transcriptomic alterations in the tumor cell using RNA sequencing. (2) Can we mechanistically understand the crosstalk between altered inflammatory axis signaling and estrogen receptor signaling in ER+ breast cancer models? We hypothesize that the inflammatory cytokines and chemokines present in the breast microenvironment alter ER signaling through the estrogen- sensitive NF-kB / IL-6 / STAT3 inflammatory axis, and this may be a novel therapeutic target for treating elderly breast cancer. (3) Does pharmacological modulation of this pathway using low-cost, well-tolerated, readily available drugs result in stunted ER+ breast cancer growth? This proposal will ultimately lead to a better understanding of the unique molecular drivers of ER+ breast cancer in the elderly. Successful completion of these Aims will provide the foundation for future studies and clinical trials to better define treatment standards for elderly patients, who are traditionally both understudied and underrepresented in clinical trials. Further, this proposal will provide me with an exemplary translational platform and research training, working with a collaborative group of clinicians and scientists to launch my career a...