title: Gasdermin-B promotes invasion and metastasis in breast cancer cells.
abstract: Gasdermin B (GSDMB) belongs to the Gasdermin protein family that comprises four members (GSDMA-D). Gasdermin B expression has been detected in some tumor types such as hepatocarcinomas, gastric and cervix cancers; and its over-expression has been related to tumor progression. At least four splicing isoforms of GSDMB have been identified, which may play differential roles in cancer. However, the implication of GSDMB in carcinogenesis and tumor progression is not well understood. Here, we uncover for the first time the functional implication of GSDMB in breast cancer. Our data shows that high levels of GSDMB expression is correlated with reduced survival and increased metastasis in breast cancer patients included in an expression dataset (>1,000 cases). We demonstrate that GSDMB is upregulated in breast carcinomas compared to normal breast tissue, being the isoform 2 (GSDMB-2) the most differentially expressed. In order to evaluate the functional role of GSDMB in breast cancer two GSDMB isoforms were studied (GSDMB-1 and GSDMB-2). The overexpression of both isoforms in the MCF7 breast carcinoma cell line promotes cell motility and invasion, while its silencing in HCC1954 breast carcinoma cells decreases the migratory and invasive phenotype. Importantly, we demonstrate that both isoforms have a differential role on the activation of Rac-1 and Cdc-42 Rho-GTPases. Moreover, our data support that GSMDB-2 induces a pro-tumorigenic and pro-metastatic behavior in mouse xenograft models as compared to GSDMB-1. Finally, we observed that although both GSDMB isoforms interact in vitro with the chaperone Hsp90, only the GSDMB-2 isoform relies on this chaperone for its stability. Taken together, our results provide for the first time evidences that GSDMB-2 induces invasion, tumor progression and metastasis in MCF7 cells and that GSDMB can be considered as a new potential prognostic marker in breast cancer.
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Hergueta-Redondo
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sarrió
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Molina-Crespo
authors.affiliation: Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Megias
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Mota
authors.affiliation: Hospital MD Anderson Cancer Centre, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rojo-Sebastian
authors.affiliation: Fundación MD Anderson Internacional, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: García-Sanz
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Saleta
authors.initials: S
authors.lastname: Morales
authors.affiliation: Hospital MD Anderson Cancer Centre, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Abril
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Cano
authors.affiliation: Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Héctor
authors.initials: H
authors.lastname: Peinado
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain; Fundación MD Anderson Internacional, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D066264:Datasets as Topic; D004195:Disease Models, Animal; D005260:Female; D005780:Gelatin / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D008875:Middle Aged; D057054:Molecular Imaging; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D011485:Protein Binding; D059748:Proteolysis; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000094524:Gasdermins
chemical_list: D005780:Gelatin; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D020741:rho GTP-Binding Proteins; C527978:GSDMB protein, human; D000094524:Gasdermins