FGFR2 Promotes Breast Tumorigenicity through Maintenance of Breast Tumor-Initiating Cells

Abstract

Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells) and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.

Preclinical Efficacy of the Auristatin-Based Antibody–Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors

“…FGFR2 aberrations, such as gene amplifications as well as protein and RNA overexpression, have been implicated in the development and progression of multiple cancer types and are commonly associated with poor prognosis and resistance to cancer treatments (7,(9)(10)(11)13). FGFR2 is highly expressed in several cancers and exhibits only restricted expression in normal tissues and organs, making it a valuable cancer target and an ideal candidate for the development of an ADC.…”

“…Oncogenic FGFR2 functions, promoted by FGFR2 overexpression, gene amplification, gene fusions, and autoactivating mutations of the receptor, have been described in several cancers, including gastric, breast, and ovarian cancer (7)(8)(9)(10)(11)(12)(13)(14). FGFR2 gene amplification is found in 4% of triple-negative breast cancers (TNBC) and appears to promote breast tumorigenicity by maintaining breast tumorinitiating cells (11,14). In gastric cancer, FGFR2 is amplified in 5% to 10% of tumors, and FGFR2 mRNA overexpression is associated with poor overall survival (9).…”

Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation

“…RNA-Seq assessment of the transcriptome after miR-515-5p overexpression revealed that genes that positively regulate Wnt signaling and also contain the seed region for miR-515-5p interaction in their 3 0 -UTRs were significantly downregulated (Supplementary Table S7). In addition, other important oncogenes that contain a miR-515-5p seed region and were downregulated by this miRNA, include FGFR2, which promotes breast tumorigenicity through maintenance of breast tumor-initiating cells (27), and interleukin-6 receptor (IL-6R), which induces STAT-3 activation and the production of the antiapoptotic proteins bcl-xl and BCL2 (36).…”

“…BCL9 improves b-catenin-mediated transcription (22); DIXDC1 targets p21 and cyclin D1 through the activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway (23); FRAT2 activates b-catenin-TCF signaling pathway (24); FZD4 is a mediator of the ERG oncogene-induced Wnt signaling (25); and TCF7L1 is a transcription factor activated by b-catenin that mediates Wnt signaling (26). In addition, we identified important genes that have been shown to promote breast cancer, such as FGFR2 and PIK3C2B (27,28), and these seem to be directly regulated by miR-515-5p. We further validated miR-515-5p-mediated regulation of a few of these genes (TCF7L1, FGFR2, and PIK3C2B) by using qRT-PCR (Fig.…”

Targeting FGFR Signaling in Cancer

“…Many FGFR1-amplified breast cancer cell lines are addicted to FGFR1 amplification (45,48,49), and FGFR1 amplification also drives resistance to endocrine therapy (48). FGFR2 amplification (4% of triple-negative breast cancer, 4%-9% of gastric cancers) is associated with the maintenance of tumor-initiating cells (50), poorer prognosis (51,52), and high sensitivity to FGFR inhibitors (49,50,53).…”