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. 2020 Oct;183(3):585-598.
doi: 10.1007/s10549-020-05763-7. Epub 2020 Jul 24.

Loss of progesterone receptor is associated with distinct tyrosine kinase profiles in breast cancer

Andliena Tahiri  1   2 , Xavier Tekpli  3   2 , Somisetty V Satheesh  4 , Rik DeWijn  5 , Torben Lüders  1   2 , Ida R Bukholm  6 , Antoni Hurtado  7   8 , Jürgen Geisler  2   9 , Vessela N Kristensen  10   11
Affiliations

Loss of progesterone receptor is associated with distinct tyrosine kinase profiles in breast cancer

Andliena Tahiri et al. Breast Cancer Res Treat. 2020 Oct.

Abstract

Purpose: The 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 design: Pamchip® 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.

Results: In 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.

Conclusions: Our 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.

Keywords: Breast cancer; ER; HER2; PI3K; PR; Tyrosine kinase.

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Conflict of interest statement

Rik DeWijn works for Pamgene. No potential conflicts of interest were disclosed by the authors.

Figures

Fig. 1
Fig. 1
Unsupervised analysis showing phosphorylation profiles of tyrosine kinase substrates in a 29 primary ER-positive breast cancer tumors and b ER-positive breast cancer cell lines, MCF7, BT474, and ZR75-1, before (E0) and after (E10) treatment with estradiol (E). The heatmap visualizes log2-transformed signal intensities retrieved from tyrosine kinase substrate arrays incubated with sample lysates, in which the samples (horizontal axis) and 104 peptides (vertical axis) are sorted according to principles of hierarchical clustering. Red corresponds to higher and blue to lower kinase substrate phosphorylation levels. ER− estrogen receptor, PR− progesterone receptor, and HER2− human epidermal growth factor receptor 2
Fig. 2
Fig. 2
Boxplots of mean phosphorylation of peptides in cluster 1, 2, and 3 in three different ER+ cell lines and a–c and different subgroups of ER+ breast cancer samples (d–f). The three peptide clusters are the same as the peptide clusters obtained from unsupervised clustering in Fig. 1a. Statistical significance between subgroups/cell lines in each cluster is indicated by p values < 0.05 in tables. ER− estrogen receptor, PR− progesterone receptor, HER2− human epidermal growth factor receptor 2
Fig. 3
Fig. 3
Upstream kinases responsible for changes in ER+/HER2− tumors with differential PR status. There are 75 putatively affected kinases (y axis) in ER+/HER2− tumors that are negatively expressed in PR+ (i.e., positive expressed in PR−). Length of the bars indicates the value of τ for each of these kinases. (τ > 0 indicates lower activity in PR+ samples compared to PR− samples). The color of the bars indicates the specificity score. Positive score means higher expressed, whereas negative score indicates low expression of the putative kinases. The kinases on the top are more likely to be upstream, compared to the kinases at the bottom of the list
Fig. 4
Fig. 4
a Heatmap with clustering of 24 kinase-encoding genes that are differentially expressed in ER+/HER2− tumors with differential PR status. Red on the heatmap indicates higher expression levels, whereas blue indicates lower mRNA expression levels. Survival analysis of breast tumors grouped by gene expression in cluster 1 (pink) and cluster 2 (blue) are shown as Kaplan–Meier survival plots of patients whose tumors were grouped into b ER+/HER2−, c ER+/HER2−/PR−, and d ER+/HER2−/PR+. ER estrogen receptor, PR progesterone receptor, Her2 human epidermal growth factor 2
Fig. 5
Fig. 5
PGR binding sites and RNA expression in a LCK, b FGFR4, c FRK, and d MST1R through PR chip sequencing and RT-PCR in untreated MCF7 cells (veh) and in cells treated with progesterone (PG2)
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