Abstract
SummaryTriple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2–35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro. KIBRA functions co-operatively with the protein tyrosine phosphatase PTPN14 to trigger mechanotransduction-regulated signals that inhibit the nuclear localization of oncogenic transcriptional co-activators YAP/TAZ. Our results argue that the selective advantage produced by 5q loss involves reduced dosage of KIBRA, promoting oncogenic functioning of YAP/TAZ in TNBC.
Highlights
15% of patients with invasive breast cancer are diagnosed with triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression (Foulkes et al, 2010)
We have previously shown that mammary tumors driven by mouse mammary tumor virus (MMTV)Met reflect human breast cancer subtypes, including basal-like (Ponzo et al, 2009), whereas conditional deletion of Trp53 in this model (MMTV-Met;Trp53fl/+;Cre) induces mesenchymal tumors modeling the TNBC subtype claudin-low (Knight et al, 2013)
Because gene expression and copy number alteration are not always correlative, we analyzed their expression in our mouse models, finding 13 genes that were significantly decreased in tumors with loss of the minimal common region (MCR) (Figure 1C; Table S3)
Summary
15% of patients with invasive breast cancer are diagnosed with triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression (Foulkes et al, 2010). Because TNBC lacks an approved targeted therapy, the only systemic treatment is chemotherapy. This can induce a complete pathological response, TNBCs are associated with a high risk of early recurrence, and metastatic disease is virtually incurable (Denkert et al, 2017; Foulkes et al, 2010). Molecular subtyping based on gene expression has defined the majority of TNBCs as basal-like (49%–80%) (Denkert et al, 2017; Lehmann and Pietenpol, 2014; Rakha et al, 2009) or claudin-low (up to 30%) (Prat et al, 2010; Prat and Perou, 2011). With few exceptions (Weigman et al, 2012), genes conferring selective pressure for 5q loss are relatively unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
