Benjamin J. Lang , Kristina M. Holton , Martin E. Guerrero-Gimenez , Yuka Okusha , Patrick T. Magahis , Amy Shi , Mary Neguse , Shreya Venkatesh , Anh M. Nhu , Jason E. Gestwicki , Stuart K. Calderwood
{"title":"热休克蛋白 72 支持转移性乳腺肿瘤细胞外基质的生成。","authors":"Benjamin J. Lang , Kristina M. Holton , Martin E. Guerrero-Gimenez , Yuka Okusha , Patrick T. Magahis , Amy Shi , Mary Neguse , Shreya Venkatesh , Anh M. Nhu , Jason E. Gestwicki , Stuart K. Calderwood","doi":"10.1016/j.cstres.2024.04.006","DOIUrl":null,"url":null,"abstract":"<div><p>This study identified tumorigenic processes most dependent on murine heat shock protein 72 (HSP72) in the mouse mammary tumor virus-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of <em>Hspa1a/Hspa1b (Hsp72)</em> WT and <em>Hsp72</em><sup>−/−</sup> primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in <em>Hsp72</em> knockout mammary tumors compared to WT controls. <em>In vitro</em> studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the tumor growth factor-β–suppressor of mothers against decapentaplegic-3 signaling pathway and evidence of suppressor of mothers against decapentaplegic-3 and HSP72 coprecipitation, suggesting potential complex formation. Human <em>COL1A1</em> mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM-related gene and protein folding-related gene as an input to the statistical learning algorithm, <em>Galgo</em>, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 3","pages":"Pages 456-471"},"PeriodicalIF":3.3000,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000725/pdfft?md5=d45a8b83fdfc70c0e9683647429bc4ef&pid=1-s2.0-S1355814524000725-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors\",\"authors\":\"Benjamin J. Lang , Kristina M. Holton , Martin E. Guerrero-Gimenez , Yuka Okusha , Patrick T. Magahis , Amy Shi , Mary Neguse , Shreya Venkatesh , Anh M. Nhu , Jason E. Gestwicki , Stuart K. Calderwood\",\"doi\":\"10.1016/j.cstres.2024.04.006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>This study identified tumorigenic processes most dependent on murine heat shock protein 72 (HSP72) in the mouse mammary tumor virus-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of <em>Hspa1a/Hspa1b (Hsp72)</em> WT and <em>Hsp72</em><sup>−/−</sup> primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in <em>Hsp72</em> knockout mammary tumors compared to WT controls. <em>In vitro</em> studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the tumor growth factor-β–suppressor of mothers against decapentaplegic-3 signaling pathway and evidence of suppressor of mothers against decapentaplegic-3 and HSP72 coprecipitation, suggesting potential complex formation. Human <em>COL1A1</em> mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM-related gene and protein folding-related gene as an input to the statistical learning algorithm, <em>Galgo</em>, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.</p></div>\",\"PeriodicalId\":9684,\"journal\":{\"name\":\"Cell Stress & Chaperones\",\"volume\":\"29 3\",\"pages\":\"Pages 456-471\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-05-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1355814524000725/pdfft?md5=d45a8b83fdfc70c0e9683647429bc4ef&pid=1-s2.0-S1355814524000725-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Stress & Chaperones\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1355814524000725\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Stress & Chaperones","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1355814524000725","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors
This study identified tumorigenic processes most dependent on murine heat shock protein 72 (HSP72) in the mouse mammary tumor virus-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of Hspa1a/Hspa1b (Hsp72) WT and Hsp72−/− primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in Hsp72 knockout mammary tumors compared to WT controls. In vitro studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the tumor growth factor-β–suppressor of mothers against decapentaplegic-3 signaling pathway and evidence of suppressor of mothers against decapentaplegic-3 and HSP72 coprecipitation, suggesting potential complex formation. Human COL1A1 mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM-related gene and protein folding-related gene as an input to the statistical learning algorithm, Galgo, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.
期刊介绍:
Cell Stress and Chaperones is an integrative journal that bridges the gap between laboratory model systems and natural populations. The journal captures the eclectic spirit of the cellular stress response field in a single, concentrated source of current information. Major emphasis is placed on the effects of climate change on individual species in the natural environment and their capacity to adapt. This emphasis expands our focus on stress biology and medicine by linking climate change effects to research on cellular stress responses of animals, micro-organisms and plants.