Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins

Abstract

Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

“…FGFRs were also shown to mediate cell survival and motility in numerous cancer types. [9][10][11][12] Promotion of oncogenesis by the FGF-FGFR signaling pathway is known to be mediated through mechanisms such as gene amplification, somatic mutations, translocations and increased expression of FGFs and/or FGFRs. 8,9,12 Amplification of the FGFR1 locus at chromosome 8p in particular was described in several cancer types, [12][13][14] such as breast, esophageal and head and neck carcinomas.…”

“…5,6,15 Furthermore, FGFR1 amplification represents a therapeutically tractable molecular event, as a selective inhibitor of the FGFR activity caused G1 growth arrest in breast cancer cell lines. 10 In SCLC, inhibition of the FGFR resulted in blockade of tumor growth, suggesting the important role of the FGF-FGFR signaling pathway for SCLC growth 16 and a recent survey of potential oncogenic driver mutations also suggested FGFR1 as a potential therapeutic target. 17 Different FGFR1 inhibitors are currently in phase I and II clinical trials such as BGJ 398 (Novartis), AZD 4547 (AstraZeneca), TKI 258 (Novartis), and BIBF 1120 (Boehringer-Ingelheim).…”

Targeting fibroblast growth factor receptor 3 enhances radiosensitivity in human squamous cancer cells

“…Because HSC-2 cells were incubated for a longer time with siFGFR3, they became more radiosensitive (Figure 1c), suggesting that radiosensitization of HSC-2 cells may be determined by the amount of FGFR3 protein in the cells at the time of irradiation. PD173074, the pharmacological FGFR inhibitor, is a synthetic compound of the pyrido(2,3-d)pyrimidine class that inhibits tyrosine kinase activities and inhibits several FGFR families including FGFR3 in human cancer cells (Koziczak et al, 2004;Trudel et al, 2004). In addition, because FGFR3 signals partly through the Ras/mitogen-activated protein kinase pathway (MasihKhan et al, 2006), we assessed the effect of the inhibitors on ERK phosphorylation.…”

Humanization of fibroblast growth factor 1 single‐chain antibody and validation for its antitumorigenic efficacy in breast cancer and glioma cells

“…It was also critical for the development of different cancers 2, 3, 4. Thus, FGF‐1 has been proposed to be a cancer therapy target, and this approach has been validated using specific inhibitor of FGF receptor (FGFR) 5, 6. Monoclonal antibody‐mediated immunotherapy is an accepted treatment modality by FDA and has shown great potential in clinical settings 7, 8.…”