||5R01CA253450-02 Interpret this number
||Univ Of North Carolina Chapel Hill
||P53, DNA Repair Imbalance, and Immune Response in Breast Cancer Mortality Disparities
Genome stability is determined by multiple DNA repair pathways, including both error-prone and error-free
mechanisms. Mutations can be caused by inactivation of DNA repair pathways (e.g. BRCA1 defects) or by
pathological activation of error-prone repair. The tumor suppressor p53 has pleiotropic effects on this balance.
It physically interacts with base excision repair (BER), modulates nucleotide excision repair (NER), and
regulates mismatch repair (MMR). Wild type p53 may inhibit error prone, but not error-free non-homologous
end joining (NHEJ), and can modulate homologous recombination (HR). Recently, new roles for p53 have
been identified, such as a role in APOBEC3B activation. Many mechanistic studies have studied the complex
roles of p53 in DNA repair, but few large-scale studies of human tumors have investigated p53 and DNA repair
pathway function in human tumors, and even fewer have evaluated these relationships by race. A more refined
understanding of the relationships between p53 loss, DNA repair, and mutational signatures is now possible
due to: (1) the advent of mutational signatures, which can provide DNA evidence of the functional effects and
balance across multiple error prone and error free DNA repair pathways; and (2) recent improvements in
expression profiling from formalin-fixed paraffin embedded (FFPE) samples. These advances are important for
understanding breast cancer mortality disparities because they enable broad scale study in population-based
resources. Our previous population-based studies have shown that p53 mutations are more common in African
American breast cancer patients (60% p53 mutant vs. 35% among white breast cancer patients). Furthermore,
DNA repair is critical for response to chemotherapy, both due to direct effects of DNA repair on chemotherapy
resistance, and indirect effects on activation of immune responses. The current project will use an integrative
approach to evaluate p53-related DNA repair pathway irregularities in human tumors, measuring both RNA
expression and mutational signatures (Aim 1a). Then, p53 loss and DNA repair imbalance will be evaluated in
relation to immune activation using both RNA and protein-based, spatial assays of immune markers (Aim 1b).
These analyses will leverage, the Carolina Breast Cancer Study (CBCS), a study of 3000 women with breast
cancer that oversampled black women (50% black women, n=1500). To better understand the germline
determinants of black-white differences in DNA repair, existing genome wide SNP data will be used to identify
genetic variants linked with DNA repair imbalance and immune response (Aim 2). This investigation will identify
key DNA repair and immune pathways, in context of p53 mutation status and race, that interact to cause
cancer progression and chemoresistance. The elucidation of these pathways is a key underlying step in
identifying clinical and public health interventions to reduce mortality disparities.
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