Breast Cancer Recurrence: Mechanisms and Drivers
Abstract
Challenge: This proposal investigates how dormant breast cancer cells survive and re-emerge as recurrent, metastatic tumors that have become resistant to therapy. Accordingly, this application addresses the challenge of eliminating the mortality associated with metastatic breast cancer. Rationale: Metastatic breast cancer has long been treated with the tacit assumption that the growth of metastatic tumors and primary tumors are driven by the same pathways. Recent findings, however, challenge this belief and suggest instead that human breast cancers undergo significant evolution during metastatic recurrence. Understanding these differences could identify potential new drug targets that might hold the key to developing more effective therapies to prevent or treat recurrent metastatic breast cancer. Accordingly, it is imperative that we identify pathways that drive the recurrence of treatment-resistant metastatic breast cancers in order to focus drug development on this critical area of need. To elucidate the molecular drivers of metastatic breast cancer growth and therapy resistance, we recently published a genome-wide comparison of metastases in breast cancer patients with the primary tumors from which they arose in order to identify genes and pathways that are preferentially altered during metastatic recurrence. Our analysis revealed an increase in the number of copies (copy number gain) of a region on chromosome 6 that preferentially occurred in metastases compared to the primary tumors from which they arose. This region encodes a single gene: PAQR8. Strikingly, we found that PAQR8 copy number gain in metastases was mutually exclusive with mutations in the nuclear estrogen receptor in patients treated with anti-estrogen therapies, suggesting that PAQR8 may also play a role in anti-estrogen resistance, and that PAQR8 copy number gain also commonly occurred in patients treated with chemotherapy. Analysis of several additional mouse models, including preliminary functional studies, further pointed to a role for PAQR8 in promoting the survival of dormant tumor cells, development of therapy resistance, and tumor recurrence. Together, our findings suggest the exciting possibility that PAQR8 up-regulation may constitute a general mechanism by which breast cancers escape therapy, persist in a dormant state, and recur. These data are the first in vivo studies to implicate PAQR8 in human cancer. Objective: The objective of the research proposed in this application is to validate PAQR8 as a novel molecular target that promotes breast cancer recurrence by facilitating resistance to targeted agents, including anti-estrogen therapy, and by promoting the survival and recurrence of dormant tumor cells. Aims: This proposal will employ mouse models and human breast cancer cell lines to test the hypothesis that PAQR8 promotes the survival and recurrence of dormant breast cancer cells following therapy. We will also test the hypothesis that inhibiting PAQR8 will result in increased killing of dormant residual cancer cells that have survived therapy, thereby reducing the risk of cancer recurrence. Additional experiments will evaluate the role of PAQR8 in resistance to anti-estrogen therapies, and explore the cellular and molecular basis for its recurrence-promoting effects. Further studies will determine whether PAQR8 associations with therapy resistance and tumor recurrence are also seen in breast cancer patients, and whether PAQR8 expression predicts which breast cancers will respond to neoadjuvant therapy, and which tumors will recur. Collectively, these experiments will advance PAQR8 as a therapeutic target for preventing and treating therapy-resistant recurrent metastatic breast cancer. Applicability and Timeline: Results from these studies will be applicable to all breast cancer patients, since all patients are either at risk for metastatic recurrence, or have already developed metastases, and since our preliminary dat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210312
Entities
People
- Lewis A Chodosh
Organizations
- United States Army
- University of Pennsylvania