Abstract
Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported in 16–36% of HER2-positive breast cancer and its clinical impact is under discussion. We examined the biological effects of HER2-heterogeneity on mouse models and analyzed metastatic brains by RNA sequence analysis. A metastatic mouse model was developed using 231-Luc (triple negative cells) and 2 HER2-positive cell lines, namely, HER2-60 and HER2-90 which showed heterogeneous and monotonous HER2 expressions, respectively. Metastatic lesions developed in 3 weeks in all the mice injected with HER2-60 cells, and in 69% of the mice injected with HER2-90 and 87.5% of the mice injected with 231-Luc. The median survival days of mice injected with 231-Luc, HER2-60, and HER2-90 cells were 29 (n = 24), 24 (n = 22) and 30 (n = 13) days, respectively. RNA sequence analysis showed that CASP-1 and its related genes were significantly downregulated in metastatic brain tumors with HER2-60 cells. The low expression of caspase-1 could be a new prognostic biomarker for early relapse in HER2-positive breast cancer.
Highlights
Genetic heterogeneity within the same tumor has been demonstrated by exome sequencing in primary renal cell cancer
No metastasis developed in the mice injected with 231-Luc cells and a small number of metastasis was found in 1 out of 2 mice injected with human epidermal growth factor receptor 2 (HER2)-90 cells at 21 days (Figure 1a,b,e,f)
We demonstrated that the heterogeneity of HER2 expression accelerated the development of metastases which caused the poor survival of mice with heterogeneous HER2 expression (HER2-60)
Summary
Genetic heterogeneity within the same tumor has been demonstrated by exome sequencing in primary renal cell cancer. Gene expression signatures of good and poor prognoses have been detected in the same tumor in different regions [1]. Both genetic heterogeneity and nongenetic heterogeneity are usually present [2,3], which may cause a difference in the therapeutic response and biological behavior. The degree of intratumoral heterogeneity including genetic and nongenetic alterations was associated with the progression of in situ human breast cancer to an invasive phenotype [5]. Intratumoral heterogeneity was associated with the progression and metastasis of breast cancer
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.
