FGF7/FGFR2-JunB signalling counteracts the effect of progesterone in luminal breast cancer
Kamil Mieczkowski1, Kamila Kitowska1, Marcin Braun2
1Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
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.
Insights
Fibroblast growth factor receptor 2 (FGFR2) signaling disrupts progesterone receptor (PR) effects on estrogen receptor α (ER)-positive breast cancer, particularly in premenopausal women via the JunB pathway.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Estrogen receptor (ER) and progesterone receptor (PR) signaling are critical in ER-positive breast cancer (ER+ BCa).
- Fibroblast growth factor receptor 2 (FGFR2) signaling is known to influence ER activity and response to anti-ER therapies.
- The interplay between ER, PR, and FGFR2, especially concerning hormonal background and menopausal status, remains incompletely understood.
Purpose of the Study:
- To investigate the impact of FGFR2 signaling on PR-dependent behaviors in ER+ BCa cells under varying hormonal conditions.
- To elucidate the molecular mechanisms underlying the crosstalk between ER, PR, and FGFR2.
- To determine the clinical relevance of FGFR2 expression in relation to patient menopausal status and treatment outcomes.
Main Methods:
- In vitro studies using ER+ BCa cell lines treated with estrogen (E2), progesterone (P4), and FGF7.
- Analysis of ER and PR expression, activity, and complex formation.
- Assessment of gene expression changes, including ER-dependent genes like JunB.
- Retrospective analysis of clinical data correlating FGFR2 expression with progression-free survival (PFS) based on menopausal status.
Main Results:
- FGF7/FGFR2 signaling abolished P4's effects on E2-promoted growth and tamoxifen response in ER+ BCa cells.
- FGFR2 signaling modulated ER and PR expression/activity, increased ER-PR complex formation, and reversed P4-induced gene deregulation.
- Clinical data showed FGFR2's prognostic value differed by menopausal status: associated with longer PFS in postmenopausal patients but not premenopausal.
- FGFR2 correlated with JunB expression only in premenopausal patients, and JunB was essential for FGFR2 to overcome P4-induced growth inhibition.
Conclusions:
- The FGF7/FGFR2-JunB axis abrogates PR's modulatory effects on ER-associated functions in premenopausal ER+ BCa.
- This axis represents a potential therapeutic target for specific patient populations.
- Findings support the need for personalized therapeutic strategies based on FGFR2 status and menopausal status in ER+ breast cancer.
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