Project 2 Abstract Breast cancer is the second leading cause of cancer mortality in women and nearly 75% of breast tumors express estrogen receptor-? (ER) at the time of diagnosis. It is estimated that about 30-40% of ER+ breast tumors become resistant to hormone therapy, either through de novo or acquired resistance. Recent evidence suggests that inflammation plays a key role in promoting pathogenesis and acquired resistance to hormone therapies, and is considered a risk factor for breast cancer. To this end, we and others have uncovered an important mechanism linking inflammatory signaling to endocrine resistance in breast cancer through interactions between the ER and NF?B, via cytokine-induced phosphorylation of ER and direct modulation of the ER pioneer factor FOXA1. This is important because greater than 80% of the lymph node metastases and 65? 70% of distant metastases arising from ER+ primary tumors retain ER expression at the time of relapse. Also, inflammatory mediators, such as cytokines like the tumor necrosis factor alpha (TNF) or the master transcription factor NF?B and its upstream regulator IKK, are highly present in breast tumors and increase with tumor grade. We will use ER+ breast cancer patient-derived xenografts (PDXs), and FACS isolated (EpCAM+/CD49f) ER+ luminal cells isolated from multiple patients, to understand how inflammatory signaling affects ER function. Our hypothesis is that inflammatory signaling, driven by NF?B and its upstream regulator IKK, leads to altered ER function and target gene expression resulting in more aggressive tumors and an increased resistance to endocrine therapy. First we will define the transcriptional and epigenetic response of the primary tumor specimens to estrogen and cytokine induced inflammatory signaling using novel next-generation sequencing technologies (such as GRO-seq, ATAC-seq and ChIP-seq) Then we will test if the primary human tumor specimens, exhibit increased proliferation, invasion, metastasis and resistance to hormone therapy when exposed to estrogen and inflammatory cytokines. We will also test if novel inhibitors of IKK/NF?B will rescue sensitivity to hormone therapy in the tumor specimens. Bioinformatic analysis of the data we generate across many patients will allow us to identify biomarkers and/or gene signatures that are potentially prognostic of patients that have worse outcomes on endocrine therapies and/or predictive of patients who may benefit from inhibitors of NF?B signaling. Listed below are the headings for our 3 specific aims:
Aim 1 :Define the transcriptional changes and chromatin binding profiles of ER and NF?B in primary human tissues in response to E2 and proinflammatory cytokines.
Aim 2 :Determine the biological consequences of inflammation-based modulation of ER function in breast tumors Aim 3:Define prognostic signatures, identify biomarkers and measure prevalence of inflammation-based modulation of ER function across patient samples.
In ER+ breast cancer, crosstalk between inflammatory signaling and estrogen signaling may play a key role in promoting more aggressive tumors and resistance to hormone therapy. This proposal is aimed at defining the genome-wide and signaling consequences of estrogen and inflammatory interplay in breast cancer patient tumor samples and determining if exposure to mediators that promote inflammation contribute to oncogenic phenotypes and endocrine resistance. These translational data will identify unique gene expression and signaling alterations induced by inflammatory and estrogen receptor crosstalk. The signatures will be tested in clinical data sets and will potentially reveal new therapeutic avenues for resistant ER+ disease.
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