Abstract
PurposeThe aim of this study was to assess protein tyrosine kinase profiles in primary breast cancer samples in correlation with the distinct hormone and growth receptor profiles ER, PR, and HER2.Experimental designPamchip® microarrays were used to measure the phosphorylation of 144 tyrosine kinase substrates in 29 ER+ breast cancer samples and cell lines MCF7, BT474 and ZR75-1. mRNA expression data from the METABRIC cohort and publicly available PR chip-sequencing data were used for validation purposes, together with RT-PCR.ResultsIn ER+ breast tumors and cell lines, we observed that the loss of PR expression correlated to higher kinase activity in samples and cell lines that were HER2−. A number of kinases, representing mostly proteins within the PI3K/AKT pathway, were identified as responsible for the differential phosphorylation between PR− and PR+ in ER+/HER2− tumors. We used the METABRIC cohort to analyze mRNA expression from 977 ER+/HER2− breast cancers. Twenty four kinase-encoding genes were identified as differentially expressed between PR+ and PR−, dividing ER+/HER2− samples in two distinct clusters with significant differences in survival (p < 0.05). Four kinase genes, LCK, FRK, FGFR4, and MST1R, were identified as potential direct targets of PR.ConclusionsOur results suggest that the PR status has a profound effect on tyrosine kinases, especially for FGFR4 and LCK genes, in ER+/HER2− breast cancer patients. The influence of these genes on the PI3K/AKT signaling pathway may potentially lead to novel drug targets for ER+/PR− breast cancer patients.
Highlights
Breast cancer is a complex disease, and depending on the molecular profiles of the tumor, it can be classified into several distinct intrinsic subtypes with different prognostic1 3 Vol.:(0123456789)Breast Cancer Research and Treatment (2020) 183:585–598 outcome [1, 2]
We report a comprehensive analysis of tyrosine kinase activity in hormone receptor (HR)-positive breast tumors that are either human epidermal growth factor receptor 2 (HER2)+ or HER2−
Microarrays were used to profile the phosphorylation of substrate kinases in the primary tumors of estrogen receptor (ER)+ breast cancer patients that were either HER2+ or HER2−
Summary
Breast cancer is a complex disease, and depending on the molecular profiles of the tumor, it can be classified into several distinct intrinsic subtypes with different prognostic1 3 Vol.:(0123456789)Breast Cancer Research and Treatment (2020) 183:585–598 outcome [1, 2]. One of the most fundamental clinical distinctions between breast cancer subtypes is whether the tumor responds to growth signaling through the hormonal (ER/PR) or HER2 receptors, as these tumors can be targeted with modern anti-hormonal or antiHER2 therapy, respectively. HER2− positive (HER2+) tumors are very heterogeneous, and in many cases, the overexpression of HER2 is associated with the loss of both ER and PR expression, but for 10% of breast cancers, both ER and HER2 are co-expressed [11]. Women with both HER2- and HR-positive cancers do have a tendency to exhibit early resistance towards endocrine therapy [12]. To our knowledge, profiling of a large number of PTKs in primary breast cancer specimens has not previously been performed, and will add valuable information regarding the aspect of molecular profiles of breast tumors, and will be important in identifying important biomarkers for clinical intervention
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