Inflammatory breast cancer (IBC), the most lethal form of breast cancer, is a health disparity. IBC has a greater incidence and younger presentation in African Ancestry women (AA) compared with white women (W). IBC is also particularly aggressive in AA, who exhibit substantially shorter median survival compared to W, irrespective of molecular subtype. The underlying causes of this disparity in clinical outcome, much of which remains after controlling for medical coverage and treatment access, are poorly understood, severely limiting potential strategies to close this gap. Our proposed work addresses the critical, unanswered questions - What tumor biological mechanisms drive the more aggressive IBC biology in AA) and how can these mechanisms be modulated therapeutically? Our epidemiological studies identify that modifiable risk factors like reproductive factors (early age at first pregnancy, multiparity, and lack of breastfeeding) and high body mass index (BMI), are associated with poor therapeutic outcomes and survival among AA-IBC compared to W-IBC. These stressors have the potential to cause persistent inflammation in the mammary gland. A basic survival mechanism that is intrinsic in both normal and cancer cells is the ability to constantly respond and adapt to stress stimuli (like mutations, life-stressors, environmental changes, therapy) referred to as adaptive stress response (ASR). Linking these observations, is our identification of ASR gene sets in IBC cells exposed to stress stimuli that show race-specific differences in expression. These datasets lead to our overarching hypotheses that 1. a heightened adaptive stress response consisting of NFκB activation, suppression of programmed cell death, and pro-tumorigenic macrophages promotes outgrowth of invasive, metastatic and treatment resistant tumor cells in AA-IBC; 2. pharmacologic inhibition of the ASR pathway in conjunction with macrophage inhibition will suppress IBC growth and dissemination. To test this hypothesis, we propose Aims to (1) investigate whether AA- and W- derived normal breast epithelial cells and IBC cell lines promote monocyte differentiation using a panel of immortalized cell lines from core breast biopsies of AA and W healthy women and IBC cells in co-culture assays with monocytes and how ASR pro-survival markers correlate with stromal patterns of stem cells and macrophages in patient tissues by gene expression and immunohistochemistry analysis; (2) implant AA- and W- patient derived IBC cell lines with differential NFκB activity in a novel macrophage-induced “early lesion” murine model to spatially query tumor-stromal cell interactions and host macrophage infiltration during tumor initiation; (3) investigate the ability of clinically available agents, birinapant, a “cell death booster” and zoledronic acid, a macrophage depleting agent to inhibit growth of tumor organoids derived from AA-IBC drug resistant variants in the ‘early lesion’ murine model. Successful compl...