Functional characterisation of a novel BRCA1-mRNA splicing complex that is mutated in multiple cancers.

Women who are born with an inherited mutation in the BRCA1 gene have a very high lifetime risk of developing breast and ovarian cancer. These women tend to have a strong family history of breast cancer and can develop breast cancer at a young age. Additionally, a large proportion of breast cancer that develop sporadically (non-inherited breast cancers) have lost the function of the BRCA1 gene. BRCA1s primary role in cells is to repair and maintain DNA and by doing this BRCA1 protects cells from being able to turn into cancers. However, the exact mechanisms through which BRCA1 protects and repairs damaged DNA remain unknown. Nevertheless, recently there have been significant advances in how BRCA1 related cancers are treated with the advent of "targeted" cancer therapies called PARP inhibitors that specifically kill cancers like BRCA1 linked cancers that have defects in their ability to repair damaged DNA.
We have recently identified a new function for BRCA1 where it, with the help of other proteins called mRNA splicing proteins, helps cells to repair damaged DNA by regulating the levels of DNA repair proteins within a cell and ensuring there is enough of these proteins to repair DNA that has been damaged. Recently, a number of mutations have also been found in a significant proportion of breast, ovarian and haematological cancers in the mRNA splicing proteins that help BRCA1 carry out this new function.

The proposed research in this project aims to:
1) Identify if and how hereditary mutations in BRCA1 affect this new function of BRCA1 helping us to understand whether this new function of BRCA1 really plays a role in the development of hereditary cancers.
2) Identify which DNA repair proteins that BRCA1 and the other mRNA splicing proteins, regulate are important for BRCA1 to carry out it's DNA repair functions.
3) Understand how cancer associated mutations in the mRNA splicing proteins that help BRCA1 repair damaged DNA affect the way these proteins are able to help BRCA1 repair damaged DNA and how they affect the way that cancers respond to different treatments.

The proposed research will add significantly to our understanding of how BRCA1 works to prevent the development of cancer. Additionally, this research may lead to the development of new tests to help decide which treatments specific cancer patients will benefit from and may also identify new proteins associated with cancer that could be targeted for future therapies.

BRCA1 is mutated in a large proportion of familial breast and ovarian cancers. Additionally, BRCA1 is lost or inactivated in a large proportion of sporadic breast and ovarian cancers. BRCA1 deficient tumours are sensitive to a range of DNA damaging chemotherapies. Indeed BRCA1 mutation is currently being used as a means of enriching early phase clinical trials for response to PARP inhibitors, a novel class of agents that specifically target DNA repair deficient cancers.

We have recently identified a novel BRCA1-mRNA splicing complex that is mutated in multiple cancer types. This complex is involved in mRNA splicing of a specific subgroup of genes following DNA damage and promotes cellular resistance to DNA damaging agents, DNA repair and maintenance of genomic stability. By carrying out these functions this complex broadly functions to suppress tumorigenesis. The main objectives of the proposed research are :
1) Identify if and how known pathogenic mutations in BRCA1 affect the functions of this complex. 2) Identify which splicing target genes of the complex are required for it's ability to promote resistance to DNA damage and DNA repair.3) Characterise how confirmed driver mutations identified within SF3B1, a component of this novel complex mutated in breast, ovarian, and myeloid malignancies, affect the function of this complex, particularly with respect to sensitivity to DNA damaging therapies. This last aim also has the potential to confirm SF3B1 mutations as potential predictors of response to DNA damage based chemotherapy.

Our current finding suggest that mutations in components of the BRCA1-mRNA splicing complex may also predict response to DNA damaging chemotherapy or novel agents such as PARP inhibitors. In addition, the confirmation of functionally and clinically relevant targets modulated by this complex will add significantly to our understanding of BRCA1 biology and may open up additional opportunities for drug development in breast cancer.

Breast cancer remains the most common cause of female cancer death in the UK. To date the major therapeutic target in breast cancer remains the estrogen receptor (ER), expressed in approximately 70% of breast cancers. However, the majority of BRCA1 related breast cancers do not respond to ER targeted therapies. Given the poor clinical outcomes and lack of targeted therapy for this subtype, a better understanding of the biology underlying this disease is required in order to develop novel therapeutic strategies and new predictive markers of response to existing and novel therapies.

We have recently identified a novel BRCA1-mRNA splicing complex that functions to regulate the stability of a specific subset of mRNA transcripts following DNA damage. We have further confirmed that disruption of this complex, results in sensitivity to DNA damage, a loss of DNA repair and genomic instability. Furthermore, driver mutations within a component of this complex, SF3B1, have recently been identified in approximately 5% of sporadic breast cancers. Consistent with this we have also demonstrated the presence of similar mutations in approximately 4% of sporadic ovarian cancers. Finally, mutations within additional members of the complex have also been reported in a range of myeloid malignancies.
A significant body of evidence exists demonstrating that BRCA1 deficient tumours are sensitive to a range of DNA damaging chemotherapies. Indeed BRCA1 mutation is currently being used as a means of enriching early phase clinical trials for response to PARP inhibitors, a novel class of agents that specifically target DNA repair deficient cancers. Our current findings suggest that mutations in components of the BRCA1-mRNA splicing complex may also predict response to DNA damaging chemotherapy or novel agents such as PARP inhibitors. In addition, the confirmation of functionally and clinically relevant targets modulated by this complex may open up additional opportunities for drug development in breast cancer.
The identification of novel cancer associated mutations that predict for response to DNA damaging agents or novel targeted therapies has the potential to impact on the lives of future cancer patients by increasing the chance of successful treatment, and reducing unnecessary treatment with ineffective drugs (which may cause additional unwanted and deleterious side effects) by facilitating the stratification of patients for the most effective therapies. This will also have major effects on families and relatives of cancer patients though enhanced quality of life. Additionally, the stratification of patients using markers of response has the potential to reduce the cost of cancer treatment by reducing the treatment of patients with ineffective, potentially expensive, therapies thereby enhancing the effectiveness of the NHS.

This has the potential to enhance the wealth of the nation through reduced health care costs. Finally, the identification of novel potential drug targets for cancer may lead to the development of new targeted cancer therapies which may impact on the lives of future cancer sufferers and their relatives by providing new more effective cancer treatments. This has the potential to foster economic growth in the UK through increased investment and employment in cancer drug development within the UK. Additionally, as above this has the potential to enhance quality of life of patients and their relatives, through enhanced cancer care.