![]() ![]() Most attention has been dedicated to the latter, which is mainly secreted by cells to the extracellular matrix, activating cell surface FGFR. A single FGF2 mRNA can give rise to five different protein variants through alternative translation sites, with the higher molecular weight variants (HMW 34, 24, 22.5, and 22 kDa) being co-linear N-terminal extensions of the lower molecular weight variant (LMW 18 kDa). About 22 FGFR ligands have been described, with fibroblast growth factor 2 (FGF2), being one of the prototypical members of this family. This can occur through different mechanisms, including increased expression of FGFR and ligands. Genomic profiling studies have demonstrated that the fibroblast growth factor receptor (FGFR) pathway is aberrantly regulated in breast cancer. Deregulation of growth factor signaling pathways have been proposed as a potential mechanism of hormone resistance. ĭespite expressing hormone receptors, most patients develop endocrine resistance with time. We have previously demonstrated that antiprogestin-responsive mammary carcinomas show higher PRA/PRB ratios than antiprogestin-resistant variants. Two main PR isoforms have been described, PRA and PRB, which play different roles in mammary gland development. Two-thirds of breast cancers express estrogen receptor α (ERα) and progesterone receptor (PR) at the time of diagnosis and endocrine therapies that block the ERα pathway are usually the standard treatment, while PR expression is mainly used as a surrogate marker of a functional ERα. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression. 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. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. 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. We assessed FGF2 expression and localization in 81 human breast cancer samples. 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 evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. ![]() Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). Cancer Res 1997 57: 4063–4069.Endocrine resistance may develop as a consequence of enhanced growth factor signaling. AAC-11, a novel cDNA that inhibits apoptosis after growth factor withdrawal. ![]() Tewari M, Yu M, Ross B, Dean C, Giordano A, Rubin R. FIF, a nuclear putatively antiapoptotic factor, interacts specifically with FGF-2. Van den Berghe L, Laurell H, Huez I, Zanibellato C, Prats H, Bugler B. The high molecular weight isoforms of basic fibroblast growth factor (FGF-2): an insight into an intracrine mechanism. Both normal and tumor cells produce basic fibroblast growth factor. Moscatelli D, Presta M, Joseph-Silverstein J, Rifkin DB. Expression of basic fibroblast growth factor (bFGF) and FGF-receptors in human leukemic cells. Blood 1999 94: 3334–3339.Īllouche M, Bayard F, Clamens S, Fillola G, Sie P, Amalric F. A high pretreatment serum basic fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin's lymphoma. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 1999 94: 1077–1085.Īguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D et al. Basic fibroblast growth factor is expressed by CD19/CD11c-positive cells in hairy cell leukemia. Gruber G, Schwarzmeier JD, Shehata M, Hilgarth M, Berger R. ![]()
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