<p dir="ltr">Metastatic breast cancer (MBC) and consequent dormancy present a significant clinical challenge due to recurrence and relapse. It is thus pivotal to understand the mechanisms which can reawaken the dormant cancer cells into a proliferative phenotype, and to develop effective therapeutic strategies to eradicate the minimal residual disease. Fibroblast Growth Factor Receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) which is amplified in MBC and plays a key role in cancer cell plasticity. Interestingly, while dormant cancer cells also exhibit high FGFR1 expression levels; still, mere FGFR1 alone is insufficient to drive proliferation without FGF2 ligand induced receptor activation. In accordance with previous data, we report elevated levels of FGF2 in serum of mice with diet induced obesity (DIO), thereby indicating a potential link between obesity and dormancy breakage. We demonstrate that serum from obese animals, exogenous FGF2 stimulation, or constitutive stimulation through autocrine and paracrine FGF2 is sufficient to induce proliferation and drive pulmonary outgrowth of the dormant D2OR model. Additionally, blockade of FGFR signaling via FGFR kinase inhibitors prevented ligand induced outgrowth of the D2OR model. Importantly, FGFR1 overexpression in normal mammary epithelial cells also requires FGF2 signaling to induce transformation suggesting that mere FGFR1 amplification alone is not a driving event.</p><p dir="ltr">Despite elevated FGFR1 expression levels in dormant and metastatic breast cancer, FGFR kinase inhibitors have been unsuccessful in inducing a significant therapeutic response in FGFR1-amplified setting, potentially due to the inability of targeting the kinase-independent functions of FGFR1. In our study, we explored the use of G-quadruplex (G4) stabilizers as epigenetic therapeutics to limit FGFR1 expression, thus targeting both kinase-dependent and independent functions of the receptor. Our findings demonstrate that, in contrast to the FDA approved FGFR-kinase inhibitors, G4 stabilizers significantly reduce the viability of dormant cells in 3D culture models. Additionally, the G4 stabilizers effectively suppressed the expression of other oncogenes such as PDGFR and MYC, which is advantageous given the heterogeneous nature of dormant and MBC cells. The results from our findings suggest that FGF2:FGFR1 signaling acts as a key molecular mechanism in modulating dormancy and breast cancer progression. Additionally, G4 stabilizers hold promise as a novel therapeutic approach to target and eliminate dormant breast cancer cells, potentially reducing the risk of relapse and improving long-term patient outcomes.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/26339503 |
| Date | 20 July 2024 |
| Creators | Muhammad H Safdar (19180555) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/_b_FGFR1_REGULATION_IN_BREAST_CANCER_LIGAND-DEPENDENT_ACTIVATION_AND_NOVEL_TARGETING_STRATEGIES_b_/26339503 |
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