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.

Therapeutic targeting of HER2–CB 2 R heteromers in HER2-positive breast cancer

“…TMA 2 was previously described in ref. 47, and contained 138 high-grade ductal breast cancer samples obtained before treatment at the Vall d'Hebron University Hospital, Virgen del Rocío Hospital (Seville, Spain), and MD Anderson Cancer Center (Madrid, Spain) between 2003 and 2014. Of them, 39 corresponded to HER2+ cases.…”

Analysis of rs8067378 Polymorphism in the Risk of Uterine Cervical Cancer from a Polish Population and its Impact on Gasdermin B Expression

“…To date, the minor allele G of rs8067378 has been found to be a significant risk factor for cervical carcinogenesis in Han Chinese and Japanese populations [13, 29]. …”

Target highlights from the first post‐PSI CASP experiment (CASP12, May–August 2016)

“…Based on the different protein levels in cancers, human GSDMA, GSDMC, and GSDMD are considered tumor suppressors and GSDMB (CASP12 target T0948), a tumor promoter. GSDMB amplification and GSDMB overexpression lead to poor response to HER2‐targeted therapy in HER2‐positive breast cancer . The N‐terminal domain of gasdermins possesses membrane‐binding activity, whereas the C‐terminal domain autoregulates the lipid binding function.…”