Cal...
Quote: "is TNBC related to a defect in the p53 pathway? And the EPA induces apoptosis via a different cellular check / safety mechanism? Or the EPA slows cell replication enough to allow other existing pathways to function normally, resulting in apoptosis?"
As far as I know the article does not mention the p53 pathway..I am not an oncologist...This article suggests the issue is in the EPHA2 receptor protein...Which if you can block genetically ..Then you can use EPA to block inflammatory eicosanoids which support the cancer..The paper offer the hypothesis that this leads to alteration of polarity in the plasma membranes via increasing cholesterol levels and this triggers apoptosis.
Quote from the article...
"EPA has been widely tested for its benefits as a dietary supplement or as neoadjuvant therapy in cancer because of its anti-inflammatory qualities and safe toxicity profile 21–23. However, it has never been considered a mainstream approach in cancer treatment. Towards its clinical development, we performed an unbiased and high-throughput functional genomics screen to identify EPHA2, a cell surface tyrosine kinase receptor protein whose inhibition heightens the therapeutic action of EPA towards TNBC.
EPHA2 is an emerging clinical target in aggressive cancers 11. Overexpression of EPHA2 has been associated with poor prognosis in multiple cancers, including colorectal, lung, ovarian, endometrial, and pancreatic cancers 24–29, and has been demonstrated to have a biological role in controlling tumor growth and metastasis 11, 30, 31. We demonstrated that EPHA2 was highly expressed in breast cancer cell lines with a triple-negative molecular subtype. Further, in retrospective analysis of breast cancer patients, we identified specific associations between high EPHA2 expression in tumors and shorter DFS outcomes in patients with the TNBC/basal-like subtype, highlighting the clinical relevance of targeting EPHA2 in TNBC.
Our strategy of targeting EPHA2 in conjunction with EPA therapy was shown to be effective through a novel, membrane-based mechanism that controls cell viability. Cell-surface-localized EPHA2 has been implicated in the control of gap junctions and cell plasma membrane polarity, subsequently contributing to tumor migration and invasion 32, 33. Further, EPA, when incorporated into the plasma membrane, can modify lipid rafts, increase membrane compaction, modify intracellular signaling, and inhibit invasive potential 16, 34, 35. Our findings suggest that EPA combined with EPHA2 inhibition drastically increases the polarity, or rigidity, of the plasma membrane through an ABCA1-dependent accumulation of cholesterol and subsequently activates programmed cell death.'
":>) JL
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