Shelby Andrus

Introduction: Breast cancer is the leading cancer diagnosis and cause of cancer death in women¹. Most breast cancers are of spontaneous origin, but 10% arise from mutations in cancer susceptibility genes². BRCA1, a gene that plays a critical role in the repair of double-stranded breaks via homologous recombination, is a well-characterized contributor to heritable breast cancer³. While mutations can occur along the length of the gene, those in the BRCT domain are of particular interest due to its many interactions with regulatory proteins². A key mediator in the BRCA1-mediated repair pathway is CtIP, a DNA damage response protein that promotes DNA repair and genome stability through a myriad of various upstream regulators and downstream effects^2-5. Understanding this pathway and its mediators is critical to developing better treatments. Methods: Researchers have demonstrated the role of GATA3 as an upstream transcriptional regulator of CtIP in response to double-stranded breaks⁶. In healthy tissue, GATA3 has been demonstrated to promote CtIP maintenance of genome stability⁷. In cancerous breast tissue, GATA3 stimulates cancer proliferation through interactions with PARP1 and the oncogene CCND1⁷. When CtIP is unable to regulate repair mechanisms, the tumor’s mutational burden and lymphocytic infiltrate increase^{1-3, 8}. Overall, BRCA1-deficient breast cancers display a phenotype very different from breast cancers with maintained BRCA1 activity and are less responsive to conventional therapies^{2, 8}. Results: Depleting GATA3 in cancerous breast tissue reduces its interaction with PARP1 and subsequent promotion of the proliferative oncogene CCND1⁷. Researchers hypothesize that if GATA3 can be depleted in breast cancer tissue, spread and metastasis can be reduced⁷. Additionally, concurrent depletion of GATA3 and treatment with PARP inhibitors would target the same pathway at two levels, potentially halting tumor growth⁷. In a different study, researchers exploited the high mutational load and lymphocytic infiltrate of BRCA1-deficient tumors by combining anti-PD-L1/anti-CTLA4 antibodies with cisplatin to increase the patient’s endogenous anti-tumor immune response and augment the effectiveness of platinum-based therapies⁸. The antibody-chemotherapy combination produced an increase in T-cell level in the tumor stroma and draining lymph nodes⁸. The improved survival in mouse models was attributed to this response and shows promise for application in humans⁸. Conclusion: The unique phenotypes of BRCA1-defienct breast cancers require novel therapies to improve patient outcomes. Targeting CtIP, it’s regulators, and distinctive markers of these cancers shows great promise in improving current treatments and expanding future options.

1. Drost R, Jonkers J. Opportunities and hurdles in the treatment of BRCA1-related breast cancer. Oncogene. 2014;33(29):3753-3763.
2. Sharma B, Kaur RP, Raut S, Munshi A. BRCA1 mutation spectrum, functions, and therapeutic strategies: The story so far. Current Problems in Cancer. 2018. doi: 10.1016.
3. Takaoka M, Miki Y. BRCA1 gene: Function and deficiency. Int J Clin Oncol. 2018;23(1):36-44.
4. Hoa NN, Kobayashi J, Omura M, et al. BRCA1 and CtIP are both required to recruit Dna2 at double-strand breaks in homologous recombination. PLOS ONE. 2015;10(4).
5. Chandramouly G, Kwok A, Huang B, Willis NA, Xie A, Scully R. BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids. Nature Communications. 2013;4. doi:10.1038/ncomms3404.
6. Zhang F, Tang H, Jiang Y, Mao Z. The transcription factor GATA3 is required for homologous recombination repair by regulating CtIP expression. Oncogene. 2017;36(36):5168.
7. Shan L, Li X, Liu L, et al. GATA3 cooperates with PARP1 to regulate CCND1 transcription through modulating histone H1 incorporation. Oncogene. 2013;33(24):3205-3216.
8.  Hu ZI, Ho AY, McArthur HL. Combined radiation therapy and immune checkpoint blockade therapy for breast cancer. International Journal of Radiation Oncology, Biology, Physics. 2017;99(1):153-164.