RESUMO
BACKGROUND: The role of prolactin (PRL) and its receptor (hPRLR) in promoting breast tumors is debated. We recently identified a gain-of-function hPRLR variant (I146L) in four women with multiple breast fibroadenomas (MFA) and no control subject. OBJECTIVES: The specific aims were to describe this cohort of women presenting with MFA to identify and functionally characterize germline variants of hPRL/hPRLR genes and compare phenotypes of all patients. DESIGN: Ninety-five patients prospectively underwent clinical examination, breast ultrasonography, magnetic resonance imaging, and hormonal evaluation of gonadal and lactotrope functions. We analyzed hPRL/hPRLR coding sequences and made comparisons with a control population of 194 women. Functional characterization of hPRLR variants was performed. Pathology and immunochemistry were systematically carried out after surgical removal of tumors. RESULTS: One third of patients had a family history of breast disease. No hormonal imbalance was observed, except 30.7% of explosive stimulated PRL. Prolactin receptor variants were identified in exon 5 (I76V: 10 patients, eight controls) and exon 10 (one patient, no control). Both I146L and I76V variants exhibited constitutive activity. Pathology showed common fibroadenomas and identified six benign phyllodes tumors. Estrogen and progesterone receptors were detected in 85 and 98% of samples, respectively. Ki-67 median staining was less than 5%. No phenotypic difference was observed between carriers and noncarriers of either hPRLR variant. CONCLUSION: We present the largest population with MFA ever described, 15% of which had a hPRLR exhibiting basal activity in vitro. This questions the involvement of the hPRLR in MFA etiology and the potential relevance of therapeutic inhibition of PRLR signaling in patients.
Assuntos
Neoplasias da Mama/genética , Fibroadenoma/genética , Receptores da Prolactina/genética , Adolescente , Adulto , Neoplasias da Mama/diagnóstico por imagem , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Fibroadenoma/diagnóstico por imagem , Frequência do Gene , Mutação em Linhagem Germinativa , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Polimorfismo de Nucleotídeo Único , Prolactina/genética , Radiografia , Receptores da Prolactina/fisiologia , Análise Serial de Tecidos , Ativação Transcricional/genética , Ultrassonografia , Adulto JovemRESUMO
Since the end of the sixties, conservative radiosurgical treatment is the standard for unifocal breast cancers < 3 cm. Retrospective and randomised trials confirmed identical survival, but an increased second failure's rate. Impact of this local failure on survival is controversy. Different prognostic factors were identified by the authors. Local extension of the local failure and inflammatory signs, the delay of its apparition and its site (witch could difference true local failure and new tumour) the histologic type of the local failure, the phase S cells rate, the N status, and characteristics of the initial tumour such as the N status, the tumour's size. The surgical treatment of the local failure is classically the salvage mastectomy associated with immediate breast reconstruction, often by cutaneous-muscular flaps. A second conservative treatment could eventually be proposed only if breast size and radiotherapy sequels would permit a second carcinologic and cosmetic surgical treatment: wide local excision and re-irradiation, unifocal tumour < 1 cm preferentially intraductal, well differentiated without lymphovascular embole, without extensive intraductal, second new cancer (in other quadrant than the initial tumor after a long enough delay), efficient and long time survey. RMN with identification of the prognostic criteria would contribute to identify the local failure witch could benefit of an iterative conservative treatment.
