FGF7/FGFR2–JunB signalling counteracts the effect of progesterone in luminal breast cancer

Abstract

We have recently demonstrated that fibroblast growth factor receptor 2 (FGFR2)‐mediated signalling alters progesterone receptor (PR) activity and response of oestrogen receptor α (ER)‐positive (ER+) breast cancer (BCa) cell lines to anti‐ER agents. Little is known about whether the crosstalk between ER and PR, shown to be modulated by the hormonal background, might also be affected by FGFR2. Here, PR‐dependent behaviour of ER+ BCa cells was studied in the presence of oestrogen (E2) and progesterone (P4) and/or FGF7. In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2‐promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER–PR complexes; and (d) reversed P4‐triggered deregulation of ER‐dependent genes. Analysis of clinical data demonstrated that the prognostic value of FGFR2 varied between patients with different menopausal status; that is, high expression of FGFR2 was significantly associated with longer progression‐free survival (PFS) in postmenopausal patients, whereas there was no significant association in premenopausal patients. FGFR2 was found to positively correlate with the expression of JunB proto‐oncogene, AP‐1 transcription factor subunit (JUNB), an ER‐dependent gene, only in premenopausal patients. Molecular analyses revealed that the presence of JunB was a prerequisite for FGFR2‐mediated abrogation of P4‐induced inhibition of cell growth. Our results demonstrate for the first time that the FGF7/FGFR2–JunB axis abolishes the modulatory effects of PR on ER‐associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR‐targeting therapeutic strategies.

FGFR2 Controls Growth, Adhesion and Migration of Nontumorigenic Human Mammary Epithelial Cells by Regulation of Integrin β1 Degradation

“…Additionally, correlation analyses of the high- vs. low-risk healthy patients were in line with other previously published data showing that uncontrolled ECM remodelling and reorganization are characteristic for high-risk breast tissue [ 58 , 59 ]. This is particularly interesting in light of recent studies focused on context-dependent prognostic significance of FGFR2 in invasive BCa [ 23 , 24 ] and identification of highly oncogenic truncated FGFR2 variant [ 60 ]. Since clinical responses to various FGFR2 inhibitors among BCa patients have still remained highly variable, there is the need to identify and better understand co-regulators of FGFR2-dependent cellular functions at the different stages of disease progression.…”

“…HB2 cells with stable knock-down of FGFR2 were established with shRNA-based lentiviral construct as previously described [ 24 , 27 ]. HB2 FGFR2(-) cells were maintained in a medium supplemented with 0.2 µg/ml puromycin (Sigma-Aldrich).…”

“…Several genome-wide meta-analyses show that single nucleotide polymorphisms (SNPs) in FGFR2 are strongly associated with an increased risk of breast cancer (BCa) [ 20 – 22 ]. On the other hand, more recent studies demonstrated a positive association between FGFR2 and good prognosis in luminal A BCa patients, highlighting a context-dependent clinical significance of the receptor [ 23 , 24 ]. However, while the importance of FGFR2 signalling in the context of mammary gland development and BCa progression has been extensively studied, its role in the initial steps of tumorigenesis has not been elucidated.…”

FGFR2-triggered autophagy and activation of Nrf-2 reduce breast cancer cell response to anti-ER drugs

“…In silico gene expression analysis was performed by utilizing data of the METABRIC cohort, publicly available from cBioPortal™ for Cancer Genomics (Breast Cancer, METABRIC dataset) [ 37 , 38 ], as previously described [ 8 ]. mRNA levels of FGFR2 and NFE2L2 were determined using the expression microarray method and available clinicopathological characteristic was obtained.…”

“…We have also showed that the significance of FGFR2 in ER+/PR+ BCa patients depends on their menopausal status. The good prognostic effect of high expression of FGFR2 was lost in premenopausal BCa patients [ 8 ].…”