Abstract
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) regulates signaling pathways involved in cell proliferation and differentiation. Currently, the anti-tumor properties of FGFR inhibitors are being tested in preclinical and clinical studies. Nevertheless, reports on FGFR inhibitor-mediated breast cancer prevention are sparse. In this study, we investigated the anti-cancer benefits of AZD4547, an FGFR1-3 inhibitor, in ErbB2-overexpressing breast cancer models. AZD4547 (1–5 µM) demonstrated potent anti-proliferative effects, inhibition of stemness, and suppression of FGFR/RTK signaling in ErbB2-overexpressing human breast cancer cells. To study the in vivo effects of AZD4547 on mammary development, mammary epithelial cell (MEC) populations, and oncogenic signaling, MMTV-ErbB2 transgenic mice were administered AZD4547 (2–6 mg/kg/day) for 10 weeks during the ‘risk window’ for mammary tumor development. AZD4547 significantly inhibited ductal branching and MEC proliferation in vivo, which corroborated the in vitro anti-proliferative properties. AZD4547 also depleted CD24/CD49f-sorted MEC populations, as well as the CD61highCD49fhigh tumor-initiating cell-enriched population. Importantly, AZD4547 impaired stem cell-like characteristics in primary MECs and spontaneous tumor cells. Moreover, AZD4547 downregulated RTK, mTOR, and Wnt/β-catenin signaling pathways in premalignant mammary tissues. Collectively, our data provide critical preclinical evidence for AZD4547 as a potential breast cancer preventative and therapeutic agent.
Highlights
Effective prevention of breast cancer remains a significant challenge due to the heterogeneous nature of tumors that are influenced by numerous genetic and epigenetic factors
fibroblast growth factor receptor (FGFR) amplification occurs in approximately 20% of breast cancers[47, 48] and FGFR1 protein overexpression has been linked to poor clinical outcomes in patients with the Luminal A breast cancer subtype[49]
The targeted inhibition of FGFRs has emerged as a promising anti-cancer strategy, especially in breast cancers that overexpress FGFRs and/or have developed resistance to epidermal growth factor receptors (EGFRs)/ErbB2-targeted therapeutics through compensatory FGFR activation[50,51,52,53,54]
Summary
Effective prevention of breast cancer remains a significant challenge due to the heterogeneous nature of tumors that are influenced by numerous genetic and epigenetic factors. The need to explore novel agents and therapeutic targets in order to improve current preventative and therapeutic outcomes is critical To this end, fibroblast growth factor receptors (FGFRs) have emerged as www.nature.com/scientificreports/. Promising targets for anti-cancer therapeutics with particular emphasis on refractory breast cancer subtypes and cases that have developed drug resistance[8]. As a potential mechanism for the anti-cancer effects of FGFR inhibition, Pond et al.[19] reported that FGFR signaling is necessary for MaSC function[19]. Considering the close association between FGFR signaling activity and MaSC function in mammary morphogenesis, AZD4547 is a promising agent for breast cancer prevention due to its potential MaSC-targeted effects. The underlying anti-cancer mechanisms of AZD4547 require further investigation
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