Grant: CIHR - ICR / Cancer Research Society Partnership - Res. Grants - Breast Cancer

Background: Mutagenic DNA repair is a critical feature during antibody maturation. Activation-Induced cytidine Deaminase (AID) promotes antibody maturation by producing deoxyuracil (dU) in antibody genes. We showed that FAM72A promotes mutagenic DNA repair by causing degradation of UNG2, a component of base excision repair (BER). This activity causes AID-induced dUs to persist in genomic DNA, thereby promoting mutations that enhance antibody affinity, a key feature in the humoral response. This work has implications in cancer as overexpression of FAM72A, which is thought to occur in many different cancers, is predicted to promote mutagenesis by degradation of UNG2. Indeed, our ongoing work shows that FAM72A is overexpressed in many cancers, including breast cancer, and that human breast cancers that overexpress FAM72A are reduced in UNG2, consistent with our work in mice. In addition, we further show that FAM72A promotes mutations in human cancers, with the greatest effects on human breast cancer. These preliminary data implicate FAM72A in cancer. Goal: This proposal will test the hypothesis that the FAM72A gene influences breast cancer development and progression in mice. Aim 1. Assess the effects of FAM72A expression on breast cancer progression. As human breast cancers overexpress FAM72A, we tested whether FAM72A influences murine PyMG breast cancer growth. Strikingly, we found that Fam72a-overexpression reduces PyMG growth in the mammary fat pad compared to controls. Since FAM72A-overexpression promotes mutagenesis, we hypothesize that FAM72A is stimulating an inflammatory reaction causing reduced tumor growth. In this Aim, we will test this hypothesis by assessing whether FAM72A expression correlates with immune infiltration. We will then test if this effect can be exacerbated with checkpoint blockade, since immunotherapy efficacy correlates with increased tumor mutation loads. Hence, this work might suggest FAM72A as a biomarker for response to immunotherapy. Aim 2: Assess the effects of FAM72A expression on breast cancer development. As mutagenesis can promote tumor development, we will assess whether overexpression of Fam72a is sufficient to promote breast cancer development. We have generated transgenic mice that overexpress Fam72a in all tissues including breast tissue. These mice will be bred to MMTV-PyMT mice to assess if FAM72A promotes breast cancer development. As FAM72A promotes mutations made by AID, we hypothesize that FAM72A will promote mutagenesis caused by the cytidine deaminases APOBEC3A and 3B (A3A, A3B), which are homologues of AID and are linked to cancer development. Hence, we will determine if the oncogenic potential of A3A and A3B in mice is promoted by FAM72A by breeding Fam72aTg mice with Apobec3A- and Apobec3B-transgenic mice and the MMTV-PyMT mouse model to evaluate breast cancer development. Conclusion: Our data suggests that the FAM72A gene is an uncharacterized gene that promotes breast cancer and might sensitize established breast cancers to checkpoint blockade. This work will advance our understanding of the underlying molecular mechanisms that impact DNA repair and mutagenesis in cancer, which will ultimately lead to the development of novel cancer therapeutics and diagnostics.