RESUMEN
Aberrant activation of fibroblast growth factor receptors (FGFR) contributes to breast cancer growth, progression, and therapeutic resistance. Because of the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan within the extracellular matrix and that blocking hyaluronan synthesis decreases proliferation, migration, and therapeutic resistance. Furthermore, FGFR-mediated hyaluronan accumulation requires activation of the STAT3 pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent hyaluronan synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and hyaluronan levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and hyaluronan synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a protumorigenic microenvironment.
Asunto(s)
Neoplasias de la Mama/metabolismo , Ácido Hialurónico/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Receptores de Factores de Crecimiento de Fibroblastos/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Microambiente TumoralRESUMEN
Fibroblast growth factor receptor 1 (FGFR1) is an oncoprotein with known involvement in mammary tumorigenesis. To understand how FGFR1 signaling promotes mammary tumorigenesis, an inducible FGFR1 (iFGFR1) system was created previously. Previous studies have demonstrated that upon iFGFR1 activation in vivo, the epidermal growth factor (EGF) ligands amphiregulin (AREG) and epiregulin (EREG) are upregulated. Both AREG and EREG interact with the EGF receptor (EGFR). Here, we investigated whether the FGFR1-induced increase in AREG and EREG expression might coordinately increase EGFR signaling to promote mammary tumorigenesis. Treatment of mouse mammary epithelial cells with either AREG or EREG conferred a greater migratory potential, increased cellular proliferation and increased extracellular regulated kinase 1/2 (ERK1/2) activation. These effects could be blocked with the EGFR-specific inhibitor erlotinib, suggesting that they are EGFR-dependent. In transgenic mice with iFGFR1 under the control of the mouse mammary tumor virus (MMTV) promoter, iFGFR1 activation also led to increased mammary epithelial cell proliferation that was inhibited with erlotinib. Taken together, these data suggest that AREG and EREG mediate tumorigenic phenotypes by activating EGFR signaling, and that the oncogenic potential of FGFR1 requires EGFR activation to promote mammary tumorigenesis.
Asunto(s)
Neoplasias de la Mama/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Glicoproteínas/farmacología , Péptidos y Proteínas de Señalización Intercelular/farmacología , Glándulas Mamarias Humanas/efectos de los fármacos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Anfirregulina , Animales , Neoplasias de la Mama/genética , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Familia de Proteínas EGF , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Epirregulina , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Femenino , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/patología , Ratones , Ratones Transgénicos , Quinazolinas/administración & dosificación , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
The recent discovery of a novel, membrane localized progestin receptor (mPR) unrelated to the classical progesterone receptor (PR) in fishes and its subsequent identification in mammals suggests a potential mediator of non-traditional progestin actions, particularly in tissues where PR is absent. While early studies on mPR focused on final oocyte maturation in fishes, more current studies have examined mPRs in multiple mammalian systems in both reproductive and non-reproductive tissues as well as in diseased tissues. Here we review the current data on mPR in mammalian systems including male and female reproductive tracts, liver, neuroendocrine tissues, the immune system and breast and ovarian cancer. We also provide new data demonstrating mPR expression in the RAW 264.7 immune cell line and bone marrow-derived macrophages as well as mPR expression and downstream gene regulation in ovarian cancer cells.
Asunto(s)
Glándulas Endocrinas/metabolismo , Regulación de la Expresión Génica , Sistema Inmunológico/metabolismo , Hígado/metabolismo , Neoplasias/genética , Sistemas Neurosecretores/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Animales , Humanos , Neoplasias/metabolismoRESUMEN
Inflammation within the tumor microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. The cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1beta) are critical mediators of the inflammatory response. Numerous studies have also linked these cytokines to breast cancer progression. As a result, the mechanisms by which these cytokines promote breast cancer have been recently explored using both in vitro and in vivo models. The results from these studies have led to speculation regarding the possible usefulness of targeting these cytokines in breast cancer patients. This review summarizes the most recent studies pertaining to the mechanisms by which proinflammatory cytokines promote breast cancer. Furthermore, the possibilities of targeting these inflammatory mediators in breast cancer patients using inhibitors that are currently being used in the clinic for other inflammatory conditions are discussed. Understanding both the mechanisms by which inflammatory mediators promote breast cancer and the effectiveness of anti-inflammatory drugs in treating breast cancer will lead to novel therapeutic regimens to treat this devastating disease.