title: Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer.
abstract: Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.
authors.affiliation: Biochemistry Department, 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: Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sarrio
authors.affiliation: Biochemistry Department, 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: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Vicario
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bernadó-Morales
authors.affiliation: Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Martínez
authors.affiliation: Pathology Department, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rojo-Sebastián
authors.affiliation: Breast Cancer and Systems Biology Unit, ProCURE, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra-Musach
authors.affiliation: Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.|Translational Research Laboratory, MD Anderson Internacional Foundation, Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Mota
authors.affiliation: Cytogenetics Department, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Martínez-Ramírez
authors.affiliation: Pathology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: Mª Ángeles
authors.initials: MÁ
authors.lastname: Castilla
authors.affiliation: Oncology Department, MD Anderson Cancer Center, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Martin
authors.affiliation: Breast Cancer and Systems Biology Unit, ProCURE, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pernas
authors.affiliation: Biochemistry Department, 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: Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain.|Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Molecular Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Nuciforo
authors.affiliation: Pathology Department, Hospital Vall d'Hebron University, Barcelona, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.affiliation: Pathology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.|Pathology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Breast Cancer and Systems Biology Unit, ProCURE, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Pujana
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.|Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain.|Molecular Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
authors.affiliation: Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.|Translational Research Laboratory, MD Anderson Internacional Foundation, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000094524:Gasdermins
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C527978:GSDMB protein, human; D000094524:Gasdermins; C508053:ERBB2 protein, human
keywords: HER2-positive breast cancer; clinical behaviour; gasdermin B; predictive biomarker; resistance to therapy