Molecular Determinants of Inflammatory Breast Cancer

Duke University, Durham NC

Investigators

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Abstract

ABSTRACT: Inflammatory breast cancer (IBC), the most lethal form of breast cancer, has a greater incidence and younger presentation and post-partum women. IBC is also particularly aggressive irrespective of molecular subtype. The underlying causes of differences 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) 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. 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 differences in expression across subtypes. 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 young women with 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 genomically characterized normal breast epithelial cells from varying individual donors and IBC cell lines promote monocyte differentiation using a panel of immortalized cell lines from core breast biopsies of 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 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 IBC drug resistant variants in the ‘early lesion’ murine model. Successful completion of this project will lead to new treatment options for IBC patients with a high unmet medical need. Importantly, new bio-specimens, PDX and derivative cell lines and IBC-specific models resulting from the proposed work will be available to the scientific community.Â