title: Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells.
abstract: Metastatic breast cancer cells are exposed to stress of detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. The purpose of this study was to explore a link between mammosphere growth, ECM gene expression, and the protein quality control system in the endoplasmic reticulum (ER). We compared the mRNA and protein levels of ER folding factors in SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres versus adherent conditions. Publicly available gene expression data for mammospheres formed by primary breast cancer cells and for circulating tumor cells (CTCs) were analyzed to assess the status of ECM/ER folding factor genes in clinically relevant samples. Knock-down of selected protein disulfide isomerase (PDI) family members was performed to examine their roles in SUM159PT mammosphere growth. We found that cells grown as mammospheres had elevated expression of ECM genes and ER folding quality control genes. CTC gene expression data for an index patient indicated that upregulation of ECM and ER folding factor genes occurred at the time of acquired therapy resistance and disease progression. Knock-down of PDI, ERp44, or ERp57, three members of the PDI family with elevated protein levels in mammospheres, in SUM159PT cells partially inhibited the mammosphere growth. Thus, breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER protein folding machinery. Targeting ER folding factors, in particular members of the PDI family, may improve the therapeutic outcomes in metastatic breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS, 66506, USA.
authors.forename: Randi
authors.initials: R
authors.lastname: Wise
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS, 66506, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Duhachek-Muggy
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS, 66506, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS, 66506, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Zolkiewski
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS, 66506, USA. zolkiea@ksu.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Zolkiewska
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019704:Protein Disulfide-Isomerases / Q000235:genetics* / Q000378:metabolism*; D017510:Protein Folding
chemical_list: D016326:Extracellular Matrix Proteins; D019704:Protein Disulfide-Isomerases
keywords: Anoikis; Breast cancer; Endoplasmic reticulum; Extracellular matrix; Mammospheres