INVESTIGADORES
GIULIANELLI Sebastian Jesus
congresos y reuniones científicas
Título:
FGF2 stimulates breast cancer growth inducing ligand-independent estrogen and progesterone receptor interactions at MYC regulatory sequences
Autor/es:
GIULIANELLI, SEBASTIÁN; GUILLARDOY, TOMAS; PEREZ PIÑERO, CECILIA; GOROSTIAGA, MARIA ALICIA; SEQUEIRA, GONZALO; PATACCINI, GABRIELA; ABBA, MARTIN; GUERREIRO, ANA CATARINA ; BARROS, ANTÓNIO ; AMADO, FRANCISCO ; HELGUERO, LUISA A; LANARI, CLAUDIA
Reunión:
Conferencia; Hormone-Dependent Cancers. Gordon Research Conference; 2017
Institución organizadora:
Gordon Research Conference
Resumen:
Seventy percent of breast cancer patients are susceptible to endocrine therapy. Interactions between estrogen receptor alpha (ERα) and progesterone receptors (PR) at gene promoters have been recently demonstrated after hormone priming. The aim of this study was to determine whether growth factor signaling, namely that triggered by FGF2, could activate ERα-inducing ERα/PR interactions at gene promoters to mediate cell proliferation. FGF2 promoted the proliferation of MCF-7 and T47D cells by increasing phospho (p)-ERα and p-PR. Genetic and pharmacological (ICI 182780; ICI) blockade of ERα or FGFR inhibitors decreased FGF2-induced cell proliferation and hormone receptor activation. The oncogene MYC is a well-known model to study the activation of ERα and PR after ligand specific induction. We focused on the enhancer (ERα-dependent) and proximal (PR-dependent) regions of the MYC promoter using luciferase constructs, co-localization approaches, chromatin immunoprecipitation and pull-down following LC/MS assays. We demonstrated that FGF2/estrogens/progestins had a similar effect to that of activating gene expression. FGF2 increased ERα and PR isoforms recruitment to both MYC regulatory sequences. ICI or mifepristone inhibited FGF2-induced gene transcription; however, they disrupted the ERα/PR interaction in distinct manners. MYC inhibitors reduced FGF2-induced cell proliferation in MCF-7 and T47D cells, and reduced C4-HI tumor growth in vivo (a murine tumor which expresses high levels of ERα and PR and grows without hormone supply in BALB/c mice). Our data suggests that FGF2 mediates MYC expression through the activation of both ERα and PR indicating that MYC inhibitors might be used in cases of constitutive hormone receptor activation or to improve current antihormone treatment. The proteins interacting with ERα and PR at the MYC promoter sites are currently being validated.