BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells

Ma, Baochun; Guo, Wenjia; Shan, Meihui; Zhang, Nan; Ma, Binlin

doi:10.1515/biol-2020-0054

Cited by 6 publications

(2 citation statements)

References 38 publications

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“…In addition to regulating cellular processes including metabolism, growth and survival, PI3K and its downstream genes are also necessary for DNA repair 8 , 9 , 16 . PI3K signaling pathway regulates the expression, location and phosphorylation of BRCA1 to stabilize DNA DSBs repair in TNBCs 17 – 19 . Inhibition of the PI3K signaling pathway has been proven to block HR mediated DNA repair by downregulating the expression of BRCA1 and Rad51, and subsequent sensitized BRCA-proficient TNBC to PARP inhibitors 8 , 9 , 20 – 23 .…”

Section: Introductionmentioning

confidence: 99%

BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression

Liu

Wang

Zhang

et al. 2021

Sci Rep

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Poly (ADP-ribose) polymerase (PARP) inhibitors offer a significant clinical benefit for triple-negative breast cancers (TNBCs) with BRCA1/2 mutation. However, the narrow clinical indication limits the development of PARP inhibitors. Phosphoinositide 3-kinase (PI3K) inhibition sensitizes BRCA-proficient TNBC to PARP inhibition, which broadens the indication of PARP inhibitors. Previously researches have reported that PI3K inhibition induced the defect of homologous recombination (HR) mediated repair by downregulating the expression of BRCA1/2 and Rad51. However, the mechanism for their synergistic effects in the treatment of TNBC is still unclear. Herein, we focused on DNA damage, DNA single-strand breaks (SSBs) repair and DNA double-strand breaks (DSBs) repair three aspects to investigate the mechanism of dual PI3K and PARP inhibition in DNA damage response. We found that dual PI3K and PARP inhibition with BKM120 and olaparib significantly reduced the proliferation of BRCA-proficient TNBC cell lines MDA-MB-231 and MDA231-LM2. BKM120 increased cellular ROS to cause DNA oxidative damage. Olaparib resulted in concomitant gain of PARP1, forkhead box M1 (FOXM1) and Exonuclease 1 (Exo1) while inhibited the activity of PARP. BKM120 downregulated the expression of PARP1 and PARP2 to assist olaparib in blocking PARP mediated repair of DNA SSBs. Meanwhile, BKM120 inhibited the expression of BRAC1/2 and Rad51/52 to block HR mediated repair through the PI3K/Akt/NFκB/c-Myc signaling pathway and PI3K/Akt/ FOXM1/Exo1 signaling pathway. BKM120 induced HR deficiency expanded the application of olaparib to HR proficient TNBCs. Our findings proved that PI3K inhibition impaired the repair of both DNA SSBs and DNA DSBs. FOXM1 and Exo1 are novel therapeutic targets that serves important roles in DNA damage response.

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Section: Introductionmentioning

confidence: 99%

BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression

Liu

Wang

Zhang

et al. 2021

Sci Rep

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“…BRCA1 is a tumor suppressor that is involved in many DNA damage repair systems and regulates a variety of cell cycle checkpoints. Mutation and loss of function of BRCA1 observed in many cancers (especially breast and ovarian cancers) may indicate that BRCA1 deficiency leads to DNA damage accumulation and tumorigenesis (Chiou et al, 2010; B. Ma et al, 2020). BRCA1 can translocate to DNA damage sites and interact with DNA repair proteins (e.g., RAD51) (Scully et al, 1997).…”

Section: Pi3k/akt Signaling Roles In Dna Damage Repairmentioning

confidence: 99%

Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk

Alemi

Sadigh

Malakoti

et al. 2021

Journal Cellular Physiology

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The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.

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Transcriptomics analyses reveal the effects of Pentagamaboronon-0-ol on PI3K/Akt and cell cycle of HER2+ breast cancer cells

Hermawan,

Wulandari,

Yudi Utomo

et al. 2023

Saudi Pharmaceutical Journal

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BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells

Cited by 6 publications

References 38 publications

BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression

BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression

Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk

Transcriptomics analyses reveal the effects of Pentagamaboronon-0-ol on PI3K/Akt and cell cycle of HER2+ breast cancer cells

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