Functional Impacts of the BRCA1-mTORC2 Interaction in Breast Cancer

Abstract

Deleterious mutations in Breast Cancer 1 (BRCA1) are associated with an increased risk of breast and ovarian cancer. Mutations in the tandem BRCA1 C-terminal (tBRCT) protein domain disrupt critical protein interactions required for the faithful repair of DNA through homologous recombination, which contributes to oncogenesis. Our studies have identified RICTOR, PRR5, and SIN1 subunits of the mammalian target of rapamycin complex 2 (mTORC2) as interacting partners with the tBRCT domain of BRCA1 leading to the disruption of the mTORC2 complex. However, the interplay between mTORC2 signaling and BRCA1 function in the DNA damage response (DDR) remains to be determined. In this study, we used protein interaction assays to determine the binary interactions between the tBRCT domain and mTORC2 subunits, evaluated the impact of mTOR inhibition on the transcriptional function of the tBRCT, evaluated the impact of mTOR signaling on BRCA1 recruitment to DNA damage-induced foci and determined the breast cancer cell line response to mTOR inhibition dependent upon BRCA1 expression and mutation. This study determined that PRR5, RICTOR, and SIN1 could each independently interact with the BRCA1 tBRCT. Inhibition of mTORC1, but not mTORC1/2, increases BRCA1 transcriptional activation activity. Treatment with pan-mTOR inhibitor PP242 diminishes DNA damage-induced γH2AX and BRCA1 foci formation. Breast cancer cells lacking expression of functional BRCA1 are more sensitive to mTOR inhibitors. These data suggest that mTOR signaling is required for BRCA1 response to DNA damage and breast cancer cells lacking BRCA1 are more sensitive to pan-mTOR inhibition. This work suggests chemotherapeutic strategies using mTOR inhibitors could be tailored for patients that lack functional BRCA1.

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

“…Likewise, PARPi decrease PARP1-XPA associations and reduce chromatin binding of XPA, suggesting the close relationship of both BER and NER pathways [160]. There is emerging evidence of extensive interactions among proteins involved in distinct DNA repair pathways and it needs to be reflected when evaluating the cancer etiology, prognostic and predictive factors based on DNA repair and DDR [180,181]. Although the concerted action of various DNA repair pathways in tumorigenesis is postulated, there is however scarce experimental evidence on this interplay.…”

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

“…Interestingly, mTOR has also been implicated in DNA replication stress [153]. In particular, the mTORC2 subunits Rictor, PRR5, and Sin1 have recently been shown to physically interact with the tBRCT domain of BRCA1, while the use of TOR inhibitors has suggested that mTORC2 and not mTORC1 is involved in activation of BRCA1-dependent transcription [154].…”

Quantitative prediction model for affinity of drug–target interactions based on molecular vibrations and overall system of ligand-receptor

“…It is worth noting that EC50 refers to the concentration of a drug, antibody or toxicant that achieves 50% of the maximum biological effect after a specified exposure time. It was commonly used as a measure of a drug's potency [ 31 ]. Kd is often used to describe degree of binding of a compound to a particular target [ 32 ].…”