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A high Δ40p53:p53 ratio supports tumor growth, Ki67 and Sox2 elevation, and reduced doxorubicin sensitivity, while targeting Δ40p53 or combining OTSSP167 with chemotherapy improves doxorubicin 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increased mammosphere/colony formation.",{"name":70,"@type":61,"acceptedAnswer":71},"How does a high Δ40p53:p53 ratio affect doxorubicin sensitivity in vivo?",{"text":72,"@type":64},"In vehicle-treated mice, a high Δ40p53:p53 ratio increases tumor growth and stemness markers, and high Δ40p53 expression reduces tumor sensitivity to doxorubicin compared with control tumors.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},380280,1790452513,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,105,109,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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inhibits doxorubicin sensitivity in breast cancer  \nLuiza Steffens Reinhardt 1,2,3, Kira Groen 1,2, Xiajie Zhang 1,2,3, Brianna C. Morten1,2, Anna Wawruszak1,2,4 and Kelly A. Avery-Kiejda 1,2,3 ✉  \n© The Author(s) 2023  \n\n| | In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated while those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous Δ40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. Δ40p53 and Sox2 colocalisation was also detected in breast cancer specimens. Further, in cells expressing a high Δ40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high Δ40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of Δ40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting | |\n| --- | --- | --- |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  | Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin. |  |\n|  |  |  |\n|  |  |  |\n|  | Cell Death and Disease (2023)14:509; [https://doi.org/10.1038/s41419-023-06031-4](https://doi.org/10.1038/s41419-023-06031-4) |  |\n|  |  |  |\n\nINTRODUCTION  \nNearly all deaths from breast cancer are a result of resistance to treatment and the subsequent development of metastases [1] . Understanding the mechanisms that contribute to deregulated p53 activities may reveal novel avenues for increasing the sensitivity to commonly used therapies in breast cancer.  \nIn breast cancer, dysregulated p53 expression signatures are abetter predictor of outcome and chemotherapy response than TP53 mutation [2, 3], suggesting that alternative molecular mechanisms may compromise p53 function. In recent years, the complexity of p53 signalling has become increasingly apparent with the discovery that p53 is expressed as 12 isoforms whose expression is associated with clinical features and outcomes of human cancers [4–11], and whose cellular activities can modulate cell fate decisions [5, 10, 12–19] . This suggests that the imbalanced expression levels of p53 isoforms to p53 are important in cancer prognostication and may affect the response to therapies known to activate the p53 pathway, such as DNA-damaging chemotherapies. We have demonstrated that high levels of the Δ40p53 isoformsupress cellular mobility and proliferation [18], however, following doxorubicin (DOX), a high Δ40p53:p53 ratio impairs the canonical p53 DNA damage response [20] . In support of this, a study from our  \ngroup has shown that Δ40p53 is potentially associated with cisplatin response in melanoma [21] . Moreover, this variant is capable of co","cbCairPDoTvt9Ok1","https://ap.wps.com/l/cbCairPDoTvt9Ok1","pdf",6988057,16,"English","# Introduction\n# Results\n## Differential gene expression in IDCs with high versus low Δ40p53","[{\"question\":\"Why are p53 expression signatures important for breast cancer treatment response?\",\"answer\":\"The document states that dysregulated TP53 expression signatures predict chemotherapy response and survival outcomes better than TP53 mutations, indicating alternative molecular mechanisms may affect p53 function.\"},{\"question\":\"What cellular changes are associated with high Δ40p53 expression?\",\"answer\":\"High Δ40p53 is linked to downregulation of genes involved in cell differentiation and upregulation of genes related to stem cell regulation, including co-localization with stem cell markers and increased mammosphere/colony formation.\"},{\"question\":\"How does a high Δ40p53:p53 ratio affect doxorubicin sensitivity in vivo?\",\"answer\":\"In vehicle-treated mice, a high Δ40p53:p53 ratio increases tumor growth and stemness markers, and high Δ40p53 expression reduces tumor sensitivity to doxorubicin compared with control tumors.\"}]","p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer | PDF",1790239525]