Translational Significance of p53 Loss of Heterozygosity in Breast Cancer
Abstract
Her2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (Her2), which promotes growth of cancer cells. In addition, more than 70% of all Her2-positive breast cancers carry mutations in the p53 tumor-suppressor gene. Non-mutated p53 (called wild-type p53) prevents tumor formation by inducing cancer cells death and growth inhibition. At early stages of breast cancer, mutation in the p53 gene initially occurs in one allele, while the second allele retains a non-mutated p53 gene, which partially functions as a tumor suppressor. However, most cancer cells lose the wild-type gene later on during tumor progression. That process is called loss of heterozygosity or LOH. Despite the high frequency of p53 mutations in Her2-positive breast cancer, mutational or LOH status of p53 at the moment is not considered for therapy planning. It is still unclear how to treat mutant p53 breast cancer patients and whether they require specific therapeutic approaches. This is mainly due to controversial epidemiological data and lack of comprehensive studies on clinically relevant models that can faithfully recapitulate human disease development. To fill this gap, we generated a novel Her2 (also called ErbB2) mouse model that is similar to early stages of human breast cancer carrying mutant p53 only in one allele. Our preliminary studies show that common therapeutic modality such as irradiation at very early stages of breast cancer dramatically accelerates cancerogenesis only in the mutant p53 allele harboring mice and does not affect mice with both wild-type p53 alleles. Furthermore, we found in the mutant p53 mice that irradiation induces loss of the wild-type p53 allele, which correlates with dramatic increase in metastases. Importantly, irradiation does not affect metastasizing in mice that retain both wild-type p53 alleles. Thus, our data imply that in early stages of breast cancer, when tumor cells still retain the p53 wild-type allele, radiation and possibly chemotherapy can promote loss of the oncosuppressive wtp53 allele and in the long run promote cancer progression and metastases. Our data caution against the use of radiation therapy in early-stage breast cancer patients that carry mutant p53 and suggest that mutant p53 and LOH status are important markers not only for the safest choice of therapy, but also for the safest screening procedures, e.g., magnetic resonance imaging and diffuse optical tomography, rather than the standard mammography. Therefore, reducing breast cancer morbidity and mortality will require the development of new therapeutic protocols (e.g., Her2-targeted therapies, Hsp90 inhibitors, kinase inhibitors) to treat this high-risk group of patients. The experiments proposed in this application aim to determine (1) how mutant p53 affects breast cancer response to conventional genotoxic therapies with regard to p53 LOH status, (2) how the response changes at different stages of breast cancer progression, and (3) what are the short- and long-term therapeutic effects of genotoxic treatments. We will utilize of our newly generated mutant p53 mouse model to test whether different types of genotoxic interventions (radiation versus chemotherapy) similarly induce loss of the wild-type p53 allele. Also, we will examine whether genotoxic treatments at the time of pre-malignant lesion formation and in established tumors will equally enhance LOH. As an alternative to genotoxic treatments, we will test whether non-genotoxic treatments such as Her2 targeted therapies, Hsp90 inhibitors, and taxanes have less deleterious effects on wtp53 LOH. We will evaluate the consequences of p53 LOH on Her2 signaling and tumor progression depending on the p53 LOH status and investigate whether p53 LOH provides an advantage to cancer cells by enabling them to metastasize. Moreover, we will evaluate two different p53 mutations that correspond to human R175H
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610448
Entities
People
- Natalia Marchenko
Organizations
- Stony Brook University
- United States Army