Breast Cancer(BC) is the most frequently diagnosed cancer in women, an estimated 12.7% of all new cancer cases diagnosed in 2022 were BC related. The most common genetic cause of BC is mutations in BRCA1/FANCS or BRCA2/FANCD1, which are members of a genetic mechanism referred to as the Fanconi Anaemia(FA)-BRCA pathway.
The FA-BRCA pathway contains >22 genes that maintain genomic stability by primarily repairing interstrand cross-links(ICL). Germline mutations in any of the FA genes can cause Fanconi Anaemia, which is characterised by chromosomal fragility, growth defects, bone marrow failure, and predisposition to cancer. Importantly, mutations in FA genes result in increased sensitivity to DNA cross-linking agents, aiding in diagnosis, but limiting cancer treatment options.
Individuals with biallelic mutations in FANCM, a protein within the FA family have increased risk for BC, sensitivity to chemotherapy agents, infertility, premature menopause, and chromosomal instability. Clinical studies have found that heterozygous LOF mutations in FANCM are significantly associated with familial linked early-onset BC.
Despite evidence of the association between BC and FANCM, there remains the question as to whether loss of FANCM function causes an increase in BC incidence. We have made a conditional knockout mouse model to address this. We are using an Mmtv-Cre driven conditional knockout of Fancm and Tp53, to generate tumours in the mammary glands of mice.
These FANCM BC mice will be used to investigate the role of FANCM as a putative BC tumour suppressor. Mice will be observed and monitored for tumour formation, at which stage they will be sacrificed. The healthy mammary tissue and tumours will be harvested for genetic, histological, and proteomic analysis.
Addressing the link between FANCM and BC incidence, will allow new avenues for disease risk prediction, diagnosis, the identification of actionable biomarkers that predict treatment response and prevention of early onset BC.