Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells
Abstract Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplification in ER + breast cancer patients correlate with poor prognosis, and FGFR inhib...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-03-01
|
| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-024-01808-7 |
| _version_ | 1827300817841946624 |
|---|---|
| author | Feng Chi Jason I. Griffiths Aritro Nath Andrea H. Bild |
| author_facet | Feng Chi Jason I. Griffiths Aritro Nath Andrea H. Bild |
| author_sort | Feng Chi |
| collection | DOAJ |
| description | Abstract Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplification in ER + breast cancer patients correlate with poor prognosis, and FGFR inhibitors are currently being tested in clinical trials. By comparing three-dimensional spheroid growth of ER + breast cancer cells with and without FGFR1 amplification, our research discovered that FGF2 treatment can paradoxically decrease proliferation in cells with FGFR1 amplification or overexpression. In contrast, FGF2 treatment in cells without FGFR1 amplification promotes classical FGFR proliferative signaling through the MAPK cascade. The growth inhibitory effect of FGF2 in FGFR1 amplified cells aligned with an increase in p21, a cell cycle inhibitor that hinders the G1 to S phase transition in the cell cycle. Additionally, FGF2 addition in FGFR1 amplified cells activated JAK-STAT signaling and promoted a stem cell-like state. FGF2-induced paradoxical effects were reversed by inhibiting p21 or the JAK-STAT pathway and with pan-FGFR inhibitors. Analysis of patient ER + breast tumor transcriptomes from the TCGA and METABRIC datasets demonstrated a strong positive association between expression of FGF2 and stemness signatures, which was further enhanced in tumors with high FGFR1 expression. Overall, our findings reveal a divergence in FGFR signaling, transitioning from a proliferative to stemness state driven by activation of JAK-STAT signaling and modulation of p21 levels. Activation of these divergent signaling pathways in FGFR amplified cancer cells and paradoxical growth effects highlight a challenge in the use of FGFR inhibitors in cancer treatment. |
| first_indexed | 2024-04-24T16:12:22Z |
| format | Article |
| id | doaj.art-9d8a1a28a88c466a86db64bb029178e3 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-04-24T16:12:22Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-9d8a1a28a88c466a86db64bb029178e32024-03-31T11:38:54ZengBMCBreast Cancer Research1465-542X2024-03-0126111710.1186/s13058-024-01808-7Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cellsFeng Chi0Jason I. Griffiths1Aritro Nath2Andrea H. Bild3Department of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer InstituteDepartment of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer InstituteDepartment of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer InstituteDepartment of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer InstituteAbstract Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplification in ER + breast cancer patients correlate with poor prognosis, and FGFR inhibitors are currently being tested in clinical trials. By comparing three-dimensional spheroid growth of ER + breast cancer cells with and without FGFR1 amplification, our research discovered that FGF2 treatment can paradoxically decrease proliferation in cells with FGFR1 amplification or overexpression. In contrast, FGF2 treatment in cells without FGFR1 amplification promotes classical FGFR proliferative signaling through the MAPK cascade. The growth inhibitory effect of FGF2 in FGFR1 amplified cells aligned with an increase in p21, a cell cycle inhibitor that hinders the G1 to S phase transition in the cell cycle. Additionally, FGF2 addition in FGFR1 amplified cells activated JAK-STAT signaling and promoted a stem cell-like state. FGF2-induced paradoxical effects were reversed by inhibiting p21 or the JAK-STAT pathway and with pan-FGFR inhibitors. Analysis of patient ER + breast tumor transcriptomes from the TCGA and METABRIC datasets demonstrated a strong positive association between expression of FGF2 and stemness signatures, which was further enhanced in tumors with high FGFR1 expression. Overall, our findings reveal a divergence in FGFR signaling, transitioning from a proliferative to stemness state driven by activation of JAK-STAT signaling and modulation of p21 levels. Activation of these divergent signaling pathways in FGFR amplified cancer cells and paradoxical growth effects highlight a challenge in the use of FGFR inhibitors in cancer treatment.https://doi.org/10.1186/s13058-024-01808-7FGF2FGFR1p21JAK-STATStemness |
| spellingShingle | Feng Chi Jason I. Griffiths Aritro Nath Andrea H. Bild Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells Breast Cancer Research FGF2 FGFR1 p21 JAK-STAT Stemness |
| title | Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells |
| title_full | Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells |
| title_fullStr | Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells |
| title_full_unstemmed | Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells |
| title_short | Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells |
| title_sort | paradoxical cancer cell proliferation after fgfr inhibition through decreased p21 signaling in fgfr1 amplified breast cancer cells |
| topic | FGF2 FGFR1 p21 JAK-STAT Stemness |
| url | https://doi.org/10.1186/s13058-024-01808-7 |
| work_keys_str_mv | AT fengchi paradoxicalcancercellproliferationafterfgfrinhibitionthroughdecreasedp21signalinginfgfr1amplifiedbreastcancercells AT jasonigriffiths paradoxicalcancercellproliferationafterfgfrinhibitionthroughdecreasedp21signalinginfgfr1amplifiedbreastcancercells AT aritronath paradoxicalcancercellproliferationafterfgfrinhibitionthroughdecreasedp21signalinginfgfr1amplifiedbreastcancercells AT andreahbild paradoxicalcancercellproliferationafterfgfrinhibitionthroughdecreasedp21signalinginfgfr1amplifiedbreastcancercells |