P01CA240685

Epigenetic Control and Genome Organization - Overall Program Summary

Gary Stein and Janet Stein, Program Directors

Our program project is a thematically, experimentally, and operationally integrated multidisciplinary team approach to address key components of genome organization that are functionally linked to modified epigenetic control of gene expression in breast cancer.

The thematic focus and working hypothesis of our program is that genomic organization and epigenetic control of gene expression coordinately facilitate physiological regulation, including hormone responsiveness, of normal and cancer cell growth, proliferation, and cell identity.

Our highly collaborative research team established paradigm-shifting insights into parameters of nuclear organization that include:

1. Mitotic gene bookmarking by phenotypic transcription factors to control fidelity of gene expression as cells divide;
2. Relationships between fidelity of nuclear organization, transcription factor localization, and metastasis of breast cancer to bone;
3. Dynamic modifications of higher-order inter- and intra-chromosomal interactions in breast cancer cells;
4. Coordinate control of cell growth and phenotype by tissue-specific transcription factors;
5. Epitranscriptomic profiling of endocrine therapy resistant and advanced breast cancer cells in response to selective estrogen receptor modulators;
6. Noncoding RNA-mediated regulation of the aggressive breast cancer phenotype.

This application captures the scientific progress, synergy, and momentum of our research team and leverages powerful new technologies for editing the genome, visualizing cells at super resolution and in real time, and decoding higher-order genome organization.

We will use normal mammary epithelial, subtype-specific, and endocrine-resistant breast cancer cell models for discovery, then validate key findings and examine potential clinical relevance using animal models, public databases, and patient tumor specimens and organoids.

Emphasis will be on exploring molecular mechanisms that integrate multiple dimensions of epigenetic control with modified genome organization in breast cancer.

Each of the three projects focuses on a unique aspect of epigenetic control that is required for fidelity of gene expression and is compromised in breast cancer, including:

1. The pivotal role of mitotic gene bookmarking in stabilizing the normal mammary epithelial phenotype (Project 1);
2. Novel functions of bromodomain chromatin readers in endocrine therapy resistance (Project 2);
3. Contributions of the novel long noncoding RNA MANCR to deregulated genome organization in aggressive breast cancer (Project 3).

A shared resource core will support integrated bioinformatics and biostatistics analyses; standardized experimental design; cell, organoid, and in vivo models; and resource authentication to ensure scientific rigor and reproducibility.

An administrative core will maximize scientific and programmatic integration, prioritization, and oversight.

The impact of this program will be the integration of multiple levels of genome organization and of epigenetic control to understand how gene regulation is disrupted in breast cancer.

University Of Vermont & State Agricultural College

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Burlington, Vermont 054050001 United States

Single Zip Code

National Cancer Institute Program Project Applications (P01 Clinical Trial Optional) (PAR-18-290)

Amendment Since initial award the End Date has been extended from 03/31/26 to 03/31/27 and the total obligations have increased 416% from $1,678,923 to $8,667,278.