SPORE in Breast Cancer

University of North Carolina

Principal Investigator(s):

Charles Perou, PhD

H. Shelton Earp III, MD

Lisa Carey, MD

• Principal Investigator(s) Contact Information
• Overview
• Project 1: Tumor Biology and Recurrence in the Carolina Breast Cancer Study
• Project 2: Inflammation-Based Mechanisms of Hormone Therapy Resistance in Breast Cancer
• Project 3: Chemotherapy/Immunotherapy Biomarker Development for Triple Negative Breast Cancer
• Project 4: Therapeutic Approaches to Adaptive Chromatin Remodeling Underlying Breast Cancer Resistance
• Administrative Core
• Biostatistics & Bioinformatics Core
• Tissue Procurement & Pathology Core (TPP) Facility Core
• Developmental Research Program
• Career Enhancement Program

Principal Investigator(s) Contact Information

Charles Perou. PhD
The May Goldman Shaw Distinguished Professor of Molecular Oncology, Department of Genetics, and Pathology & Laboratory Medicine
UNC Lineberger Comprehensive Cancer Center
Marsico Hall 5111, 125 Mason Farm Road, CB #7599
Chapel Hill, NC 27599
(919) 843-5740

H. Shelton Earp III, MD
Director, UNC Lineberger Comprehensive Cancer Center
Director, UNC Cancer Care Lineberger
Professor of Cancer Research
Professor of Medicine & Pharma
UNC Lineberger Comprehensive Cancer Center
General Administration Suite 10-000, 450 West Drive, CB#7295
Chapel Hill, NC 27599
(919) 966-1185

Lisa Carey, MD
L. Richardson and Marilyn Jacobs Preyer Distinguished Professor for Breast Cancer Research
Deputy Director of Clinical Sciences
UNC Lineberger Comprehensive Cancer Center
General Administration Suite 10-000, 450 West Drive, CB#7295
Chapel Hill, NC 27599
(919) 843-6814

Overview

The primary objective of the UNC Breast Spore is to conduct translational research at the UNC Lineberger Comprehensive Cancer Center that will impact the outcome for breast cancer patients in North Carolina and across the nation. In order to accomplish this goal we will use our strengths in bioinformatics, immunogenomics, proteomics and population cohorts to support our teams of clinicians, public health and basic researchers.

• Project 1. Tumor Biology and Recurrence in the Carolina Breast Cancer Study
• Project 2. Inflammation-Based Mechanisms of Hormone Therapy Resistance in Breast Cancer
• Project 3. Chemotherapy/Immunotherapy Biomarker Development for Triple Negative Breast Cancer
• Project 4. Therapeutic Approaches to Adaptive Chromatin Remodeling Underlying Breast Cancer Resistance

These projects are supported by XX shared resources: Core A. The Administration Core; Core B. Biostatistics & Bioinformatics Core; Core C. Tissue Procurement & Pathology Core (TPP). The SPORE also supports a Career Enhancement Program to support junior investigators in translational breast cancer research and a Developmental Research Program to support innovative translational research.

Project 1: Tumor Biology and Recurrence in the Carolina Breast Cancer Study

Project Co-Leaders:
Melissa Troester (Basic Co-Leader)
Lisa Carey (Clinical Co-Leader)

Black women suffer higher incidence of poor-prognosis breast cancer subtypes and worse stage-specific mortality. Our previous SPORE discoveries have integrated population-based epidemiology with tumor biology to demonstrate that young and Black women are more likely to develop Basal-like tumors, Luminal B, and HER2-enriched breast tumors. Furthermore, even among the best-prognosis clinical subset of ER-positive/HER2-negative breast cancers, Black women have higher multi-gene RNA-based risk of recurrence (ROR) scores. These findings implicate tumor biology as an important contributor to racial mortality disparities. Recent research has implicated mutational processes and immune system response as two critical factors influencing susceptibility to chemotherapeutic treatment. If the relationships between mutational burden and types, immune response, and chemotherapy response were better understood, precision approaches for targeting tumors are possible. Data from resources such as the Cancer Genome Atlas project suggest vulnerabilities that could be exploited, but these large public resources tend to have limited race and age diversity. Thus, using resources from the Carolina Breast Cancer Study, a population-based study (n=3000, diagnosed 2008-2013 with invasive breast cancer) that oversampled Black and young women, we will perform molecular analysis of tumor specimens. We will sequence tumor DNA and paired normal to identify mutational signatures in Black and white women (Aim 1) and we will characterize tumor immune microenvironments using immunohistochemical markers and RNA profiling (Aim 2). We hypothesize that mutational signatures and immune responses, independently and jointly, contribute to breast cancer progression, leading to novel intervention opportunities. This project will deepen our understanding of racial differences in tumor biology and progression and seeks to reduce mortality disparities.

Project 2: Inflammation-Based Mechanisms of Hormone Therapy Resistance in Breast Cancer

Project Co-Leaders:
Hector L. Franco, PhD (Basic Co-Leader)
Albert Baldwin, PhD (Basic Co-Leader)
Claire Dees, MD (Clinical Co-Leader)

It is estimated that about 30-40% of ER+ breast tumors become resistant to hormone therapy, either through de novo oracquired 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 NFkB, 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 NFkB and its upstream regulator IKK, are highly present in breast tumors and increase with tumor grade.

We will use primary tumor specimens, ER+ 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 NFkB 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 single-cell sequencing technologies (such scRNAseq and scATAC-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/NFkB 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 NFkB signaling.

Project 3: Chemotherapy/Immunotherapy Biomarker Development for Triple Negative Breast Cancer

Project Co-Leaders:
Chuck Perou (Basic Co-Leader)
Lisa Carey (Clinical Co-Leader)

Triple-Negative Breast Cancers (TNBC = negative by clinical assays for ER, PR and HER2) are amongst the most clinically challenging tumors because of their inherent aggressive biology and lack of treatment options, which is typically limited to chemotherapy only. These tumors are more common in African American women and young women, and contribute to racial outcome disparity differences. To advance our knowledge of the biology of TNBC, we believe it critical to precisely define the biological entities that are present within this known heterogeneous group and to determine what is the driving biology of each group. This should then allow us to identify robust biomarkers of response for the most relevant therapeutics that are, or might be, used in the breast cancer clinic for TNBC patients. TNBC are composed of multiple disease subtypes including Basal-like, Claudin-low/Mesenchymal, and Luminal-type tumors. We propose a divide-and-conquer approach where we will first use a genomic biomarker strategy to segregate TNBCs into these more homogenous biological subtypes, and then target a key feature, or features, of each subtype in order to make advances for personalized medicine. For TNBC patients, chemotherapy treatment is still quite effective for many; therefore, we will continue our studies aimed at identifying the most chemotherapy responsive subset of TNBC patients. Many TNBC patients have tumors with sizable immune cell infiltrates as demonstrated by us and others. The presence of intra-tumor immune cells predicts a better prognosis, and we hypothesize this feature might also predict the benefit of immune checkpoint inhibitors as well. We propose to test these hypotheses using Genetically Engineered Mouse Models and tumor samples coming from clinical trials, and if successful validate biomarkers for chemotherapy and immune therapy responsiveness in TNBC patients in order to deliver these drugs to the subset of patients whom would benefit the most.

Project 4: Therapeutic Approaches to Adaptive Chromatin Remodeling Underlying Breast Cancer Resistance

Project Co-Leaders:
Gary L. Johnson, PhD (Basic Co-Leader)
H. Shelton Earp, MD (Clinical/Applied Co-Leader)

A hallmark of TNBC is frequent elevation of MAPK signaling (elevated expression of KRAS, BRAF) or increased copy number of receptor tyrosine kinases (RTKs). The failure of MAPK pathway directed inhibitors, which initially inhibit tumor growth, but resistance rapidly develops, shows TNBC’s remarkable resiliency and capability to overcome growth arrest by rewiring signaling networks to evade drug effects. Rapid adaptive bypass to inhibition of the MAPK pathway using trametinib to inhibit MEK1/2 occurs by a selective chromatin remodeling and transcriptional response driving resistance in a Myc-dependent process. In contrast, resistance to the HDAC inhibitor, entinostat involves a selective chromatin remodeling and a transcriptional response that is a Myc-independent process. Our objective is to block as well as reverse both Myc-dependent and Myc-independent mechanisms of chromatin remodeling that result in transcriptional changes leading to resistance. Measuring chromatin accessibility, histone acetylation and RNA expression, we identified differences in the chromatin landscape between the epithelial and mesenchymal subpopulations of TNBC, and how the landscape changed in response to therapy. Our studies provide a roadmap to block and reverse chromatin remodeling that drives adaptive resistance, which can be heterogenous in relation to gene expression changes in epithelial and mesenchymal TNBC subpopulations. In both Myc-dependent and independent resistance mechanisms the BET bromodomain protein, BRD4 is recruited to chromatin remodeling sites and BET bromodomain inhibitors reverse the recruitment by inhibiting the function of BRD4, restoring sensitivity to drug treatment. We are currently determining MAPK pathway inhibitor induced alterations in enhancer function, open chromatin states, and gene expression driving inhibitor selective adaptive bypass resistance. RNAseq combined with ATACseq (a measure of open chromatin states) of TNBC organoids treated with trametinib or entinostat alone or in combination with chromatin modifying protein inhibitors is being used to determine the heterogeneity of open chromatin states allowing differential transcriptional responses to targeted therapy. The goal is to determine the chromatin landscape of subpopulations of cells selected with drug treatment, and how to pharmacologically block adaptive and acquired chromatin states so that the primary drug treatment has a durable tumor inhibitory response.

Administrative Core

Core Directors:
Shelton Earp, MD (Co-Director)
Charles Perou, PhD (Co-Director)

The UNC Breast Cancer SPORE Administrative Core has supported the infrastructure, planning, and evaluation of the UNC Breast SPORE since 1992. The Administrative Core and its leaders Earp and Perou are responsible for the institutional long-range plans and resource commitments of the Cancer Center’s largest translational portfolio. The UNC Breast SPORE Administrative Core supports an exceptional team of breast cancer translational researchers as they explore and address minority disparities research, genomic analysis, molecular subtyping and therapeutic resistance, while advancing new technology and developing junior faculty into translational research leaders.

Biostatistics & Bioinformatics Core

Core Directors:
Steve Marron, PhD (Director)
Joseph G. Ibrahim, PhD (Co-Director)
Katherine Hoadley, PhD (Co-Director)

The services of this Core include RNA and DNA sequence data management and analysis, biostatistics, methodological development, and computational infrastructure. The capabilities in this arena at UNC Lineberger and the UNC Gillings School of Public Health are nation-leading. This SPORE Core is the most closely allied with the LCCC Bioinformatics Shared Resources and builds upon its strengths. This group has developed and applied data processing and analysis methods that are widely used across the world. The combined experience and ability of the LCCC Biostatistics and Bioinformatics Shared Resources will be available to all projects in this SPORE.

Tissue Procurement & Pathology Core (TPP) Facility Core

Core Director:
Benjamin Calhoun, MD, PhD

The UNC Breast Cancer SPORE Tissue Procurement & Pathology Core (TPP) Facility is a multifunctional facility, comprised of multiple components including Tissue Procurement and Translational Pathology. This Core provides centralized, quality controlled, quality assured procurement, processing, analysis, storage and distribution of normal and malignant breast tissue, blood specimens and other human specimens in support of basic science, translational, genomic, population and clinical trial cancer research. In addition to tissue and blood procurement services, the facility performs extraction of high quality DNA from whole blood, peripheral blood mononuclear cells, buccal smears and mouth rinses and immortalization of breast cancer patient lymphocytes.

Developmental Research Program

Program Director:
Shelton Earp, MD

The UNC Breast Cancer SPORE Developmental Research Program (DRP) has promoted novel breast cancer research across the population, translation and clinical arenas. The highly successful Program includes mechanisms for stimulating grant applications, rigorously evaluating proposals, selecting projects with advocate input, and monitoring progress. Application mechanisms include Cancer Center-wide competitive awards and rapidly emerging opportunities. Evaluation and selection processes include independent peer review, another level of external review and patient advocate committee review. The SPORE Multi-PIs, with input from the Executive Committee, make final decisions regarding selection and budget. Over the last year we have expanded a pilot process of solicitation to three UNC system Universities, our minority serving institution partner, NC Central University; our sister public medical school at East Carolina University, and our large sister institution, NC State University, with its emphasis on engineering statistics, veterinary medicine and cancer biology.

Career Enhancement Program

Program Director:
Lisa Carey, MD

Since 1992, the UNC Breast Cancer SPORE has used career development funds to promote the breast cancer research careers of selected investigators. The SPORE Career Enhancement Program (CEP) both recruits externally and identifies internal faculty with interest in translational breast cancer research. The CEP then matches junior faculty with training offerings and senior mentors. We seek to enrich the field with our efforts to promote diversity, equity and inclusion as both participants and mentors in the program.

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