PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond

De, Pradip; Carlson, Jennifer H.; Leyland‐Jones, Brian; Dey, Nandini

doi:10.1007/978-3-319-34211-5_3

Cited by 2 publications

(2 citation statements)

References 150 publications

(172 reference statements)

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“…Because the PI3K/AKT/mTOR pathway is known to directly regulate DNA damage repair in cancer cells, alterations of this pathway can be contextually connected to DNA repair defects and radioresistance (30). As ionizing radiation confers lethality through the induction of DNA double-strand breaks (DSB), the role of COASY in DNA damage repair was assessed.…”

Section: Coasy Enhances Dna Repair Efficiencymentioning

confidence: 99%

CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer

et al. 2020

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Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. Importantly, genetic overexpression and knockdown yielded radioresistant and sensitive phenotypes, respectively, in vitro and in vivo. COASY-knockdown xenografts were more vulnerable to radiation, showing delayed tumor growth, decreased proliferation, and increased apoptosis.Mechanistically, COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85a, which increased AKT and mTOR phosphorylation, enhancing cell survival. Furthermore, shRNA COASY knockdown disrupted downstream PI3K pathway activation and also hindered DNA double-strand break repair, which both led to improved radiosensitivity. Collectively, this work reveals for the first time the biological relevance of COASY as a predictive rectal cancer biomarker for radiation response and offers mechanistic evidence to support COASY as a potential therapeutic target.Significance: COASY is a novel radiotherapy response modulator in rectal cancer that regulates PI3K activation and DNA repair. Furthermore, COASY levels directly correlate with radiation response and serve as a predictive biomarker.

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Section: Coasy Enhances Dna Repair Efficiencymentioning

confidence: 99%

CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer

et al. 2020

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“…Their study demonstrated that INPP4B protein loss was also frequently co-existed in PTEN-null tumors. Interestingly, a loss of INPP4B protein was found to be a marker of the aggressiveness in basal-like breast carcinomas [ 16 , 17 ]. From the view point of cell signaling, PTEN and INPP4B control the homeostasis of the activation of the PI3K-AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Down’s Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship

Dey

Krie

Klein

et al. 2017

IJMS

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Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease.

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PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond

Cited by 2 publications

References 150 publications

CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer

CoA Synthase (COASY) Mediates Radiation Resistance via PI3K Signaling in Rectal Cancer

Down’s Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship

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