Maryam Khurram

Background: Breast cancer is the most common cancer diagnosed in women and is the second leading cause of cancer related mortality in women.¹ There are five molecular subtypes, but treatment is primarily guided by three clinical categories: Hormone Receptor + (HR+), HER2+, and triple-negative breast cancer (TNBC). TNBC is the most deadly subtype and usually treated with cytotoxic chemotherapy.² TNBC is associated with younger age, Black and Hispanic ancestry, obesity, and higher parity.²,³ Although there are multiple causes, 50-80% of TNBC cells have a deficiency in the homologous recombination (HR) repair pathway.⁴ BRCA1 is a tumor suppressor gene essential for repairing DNA double-strand breaks via HR.⁵ The most common cause of hereditary breast cancers are mutations in the BRCA1 or BRCA2 genes.¹ When this pathway is disrupted, cells become reliant on alternative repair mechanisms, such as the poly (ADP-ribose) polymerase (PARP) pathway. Targeting PARP in cells deficient in HR leads to synthetic lethality, where simultaneous loss of both DNA repair pathways results in an accumulation of DNA damage, ultimately causing cancer cell death.⁶ Thus, PARP inhibitors (PARPi) selectively kill HR-deficient cancer cells while sparing normal cells with intact repair mechanisms, making them an effective targeted therapy in TNBC with HR deficiency.

Objective: In this review, we explored specific mechanisms by which PARP inhibitors function in the treatment for TNBC breast cancer.

Methods: An online search of the PubMed database for papers published between 2017 to 2025, using the following MeSH terms: “PARP inhibitor,” and “triple negative breast cancer” was conducted.

Results: The BRCA1–BARD1 complex (BRCA1-associated RING domain protein 1) plays a central role in HR. Researchers of study 1 expressed BRCA1 and BARD1 in insect cells and used a D-loop formation assay (in vitro strand invasion assay) to assess their effect on HR. Results revealed the BRCA1–BARD1 complex enhanced the activity of RAD51, a recombinase essential for strand invasion, by increasing D-loop formation, the HR intermediate for template directed DNA synthesis. This indicates that BRCA1–BARD1 facilitates assembly of the synaptic complex, a key step in HR.⁵ A separate study showed that RNF19A, an E3 ubiquitin ligase, disrupts BRCA1–BARD1 function by ubiquitinating BARD1, leading to its cytoplasmic export and dissociation of the complex. Tumors overexpressing RNF19A responded significantly better to olaparib, a PARPi, suggesting that impaired BRCA1–BARD1 function sensitizes tumors to PARPi.⁷ In the PETREMAC Phase II clinical trial, researchers evaluated the efficacy of olaparib, a PARPi, as monotherapy in 32 treatment-naïve TNBC patients. The trial assessed the objective response rate (ORR) in relation to HR deficiency biomarkers. The ORR was 56.3%, with 88.9% of responders exhibiting HR deficiency, such as BRCA1 promoter methylation. Low RAD51 foci, indicating defective HR, were also found in responders, suggesting that RAD51 foci and methylation status may serve as predictive biomarkers for PARPi response.⁴

Conclusion: The BRCA1 pathway is a key player in the pathogenesis of breast cancer. BRCA1-deficient tumors, common in TNBC, are highly sensitive to PARPi. Clinical and in vitro studies suggest using biomarkers, like BRCA1 methylation and RAD51 foci, to select patients most likely to benefit from PARPi. Future studies should explore resistance pathways and evaluate combination therapies to enhance PARPi efficacy.

Work Cited:

1. Szczepanek J, Skorupa M, Jarkiewicz-Tretyn J, Cybulski C, Tretyn A. Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA. Int J Mol Sci. 2023;24(8):7235. Published 2023 Apr 13. doi:10.3390/ijms24087235
2. Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019;321(3):288-300. doi:10.1001/jama.2018.19323
3. Natarajan R, Aljaber D, Au D, et al. Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage. Int J Environ Res Public Health. 2020;17(2):493. Published 2020 Jan 13. doi:10.3390/ijerph17020493
4. Eikesdal HP, Yndestad S, Elzawahry A, et al. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann Oncol. 2021;32(2):240-249. doi:10.1016/j.annonc.2020.11.009
5.  Zhao W, Steinfeld JB, Liang F, et al. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature. 2017;550(7676):360-365. doi:10.1038/nature24060
6. Cruz C, Castroviejo-Bermejo M, Gutiérrez-Enríquez S, et al. RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann Oncol. 2018;29(5):1203-1210. doi:10.1093/annonc/mdy099
7. Zhu Q, Huang J, Huang H, et al. RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination. Nat Commun. 2021;12(1):6653. Published 2021 Nov 17. doi:10.1038/s41467-021-27048-3