UNRAVELING THE MUTAGENIC MECHANISMS OF BREAST CANCER
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: In 2019, approximately 250,000 women and men are expected to be diagnosed with breast cancer in US and most will be treated with surgery and chemotherapy. However, about 40,000 of these patients will develop resistance to therapy and sadly, will not survive. These stark statistics compel us to identify new treatments for this pervasive cancer. A current challenge in breast cancer research is to understand the diversity of types of cells in tumors that help protect the tumors from current chemotherapy drugs, and also allows as metastases to develop. Within the same tumor from the same patient, tumor cells might be subtly or even dramatically different, making it harder to treat clinically. A protein called APOBEC3B is a major driver of genomic modifications in breast cancers. It directly attacks DNA and rewrites genomic information, creating new types of cells within the tumor. APOBEC3B expression is protective for breast tumors because it increases diversity in the tumor, promoting disease progression and an increased resistance to chemotherapy drugs. More than 50% of patients with breast cancer have an overexpression of APOBEC3B and the higher expressions of APOBEC3B correlate with poor prognosis and lower survival rates. 
 We believe this attack of the cancer genome by APOBEC3B creates a vulnerability that can be exploited to develop new therapies that specifically target breast cancer cells without harming normal cells. Our laboratory’s goals are to determine exactly how APOBEC3B spurs these genomic changes in patients with breast cancer and to develop new strategies to specifically kill cancer cells that express APOBEC3B. Determining the function and regulation of APOBEC3B is crucial to understanding the fundamental mechanisms that cause breast cancer cells to accumulate genomic modifications and develop resistance to current therapies. This research will lay the foundation so that we can then explore drugs that have the potential to block APOBEC3B activity in breast cancers. 
 The question(s) or central hypotheses of the research: The goals of this project are to determine how APOBEC3B generates mutations in patients with breast cancer and to develop strategies to target APOBEC3B-expressing breast cancers. 
 The general methodology: To test our central hypothesis, we will use a collection of established breast cancer cell lines expressing a varied level of APOBEC3B to explore the molecular mechanisms leading to APOBEC3B overexpression in breast cancer. 
 Innovative elements of the project and potential impact: APOBEC3B expression has recently emerged to be associated with cancer susceptibility in breast cancer by generating a shower of modifications in DNA across the genome. However, the molecular mechanism behind APOBEC3B-inducing genomic changes is still poorly understood. The proposed experiments involve breast cancer cells expressing APOBEC3B to assess the functional mechanisms used by the cells to fight and protect their genome against APOBEC3B-inducing mutations. It represents a new direction of investigation in breast cancer research. We conceived a collection of unique technics to study APOBEC3B localization, interaction and activity to determine how APOBEC3B generates genomic instability and mutation in breast cancer patients. The success of this proposal would have a significant clinical impact for thousands of patients with breast cancer that overexpress APOBEC3B. The results we will be able to collect using CBCRP funding will be critical for us to apply for more substantial funding to support mouse model studies and potential future clinical investigations that move our research beyond breast cancer cell lines and into the clinic.