Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer

Abstract

Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.

<p>MicroRNA-936 targets FGF2 to inhibit epithelial ovarian cancer aggressiveness by deactivating the PI3K/Akt pathway</p>

“…FGF2 is well characterized and possesses the typical features of the FGF family, which plays significant roles in various physiological and pathological processes 33. Previous studies reported that FGF2 is strongly expressed in various tumors, such as gastric cancer,34 breast cancer,35 glioma,36 and lung cancer 37. FGF2 is also highly expressed in EOC20 and has oncogenic activity in EOC formation and progression 21–23.…”

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

“…In this study, we propose that autocrine or paracrine FGF2, probably produced by stromal CAFs, activates FGFRs and downstream signaling pathways, which in turn activate ERα and classic and novel PR isoforms. These activated receptors form complexes that play key roles inducing the transcription of MYC , a master cancer gene.…”

Construction and Analysis of Competing Endogenous RNA Networks for Breast Cancer Based on TCGA Dataset

“…Myc inhibitor, antiestrogen, or antiprogesterone can reverse the effect of FGF2 induction [ 37 ]. Ana et al studied the role of FGF2 subtype in the progression of BC by evaluating the expression and location of FGF2 in 81 cases of BC [ 38 ]. They found that FGF2 was expressed in 55.6% of breast cancer cells.…”