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

• Published in: Molecular oncology Vol. 16; no. 15; pp. 2823 - 2842
• Main Authors: Mieczkowski, Kamil, Kitowska, Kamila, Braun, Marcin, Galikowska‐Bogut, Barbara, Gorska‐Arcisz, Monika, Piasecka, Dominika, Stawiski, Konrad, Zaczek, Anna J., Nejc, Dariusz, Kordek, Radzisław, Romanska, Hanna M., Sadej, Rafal
• Format: Journal Article
• Language: English
• Published: Hoboken John Wiley & Sons, Inc 01.08.2022; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Breast cancer; Cancer therapies; Cloning; Endocrine therapy; Experiments; FGFR2; Fibroblast growth factor receptor 2; Fibroblast growth factor receptor 7; Fibroblast growth factor receptors; Fibroblasts; Gene expression; Growth factors; JunB; JunB protein; Kinases; luminal breast cancer; Medical prognosis; Menopause; Patients; Phenols; Post-menopause; Progesterone; Proteins; steroid hormones; Tumor cell lines; United States > US; Germany
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13274

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. Oestrogen receptor α (ER) and progesterone receptor (PR), in the presence of steroid hormones, form a direct complex which regulates expression of a gene set associated with a good prognosis in luminal breast cancer (BCa). Here, we suggest that FGF7/FGFR2‐triggered signalling, in the premenopausal patients, engages JunB to the transcriptionally active complex resulting in a poor BCa patient outcome.