Evaluating Interstrand Crosslink (ICL) Repair in Triple-Negative Breast Cancers To Guide Chemotherapy

As cells proliferate, they must preserve the integrity of their genome, or DNA, which carries all the information characteristic of the species. Cells have evolved highly regulated mechanisms to monitor, sense, respond to, and repair any damage occurring to the DNA molecule. Deregulation of these processes is associated with cancer development. For example, several mutations in genes involved in repairing broken DNA (BRCA) are associated with a significantly higher risk of developing breast cancer. Cancers frequently exhibit molecular alterations or 'markers' and can be stratified based on these. Treatment can be targeted by using specific drugs, which preferentially eliminate cells displaying this marker. Targeted therapy has revolutionized the treatment of breast cancers. Breast tumors are often classified using the estrogen receptor (ER), the progesterone receptor (PR), and human epithelial growth factor 2 receptor (HER2). However, no rational therapy is available for patients with breast tumors that are negative for these three molecular markers, the so-called triple negative breast cancers (TNBCs). Patients in this category have a poor prognosis; therefore, an understanding of the molecular alterations in TNBCs is urgently required for the design of a rational therapy and the identification of prognostic markers. Increasing evidence suggests that a significant fraction of TNBCs are associated with alterations in the response to DNA damage. The objective of this proposal is to characterize a set of human breast cancer cell lines for their ability to repair a very harmful type of DNA lesion called inter-strand crosslinks (ICLs). These lesions involve the linking of the two strands of the DNA molecule, thus preventing its duplication or the translation of its sequence into mRNAs and proteins. These lesions are generated by several classes of cancer chemotherapeutic agents used to treat TNBCs, which are resistant to tailored therapy. The goal is to correlate the sensitivity of the cells to crosslinking agents with their ability to repair ICLs. Ultimately, identifying characteristics associated with breast tumors that predict sensitivity to chemotherapeutic reagents and thus a successful clinical outcome should benefit breast cancer patients with the most critical need for improved therapies.