Bogorad Roman L, Courtillot Carine, Mestayer Chidi, Bernichtein Sophie, Harutyunyan Lilya, Jomain Jean-Baptiste, Bachelot Anne, Kuttenn Frédérique, Kelly Paul A, Goffin Vincent, Touraine Philippe
Institut National de la Santé et de la Recherche Médicale U845, Equipe Prl, GH et tumeurs, Centre de Recherche Croissance et Signalisation, F-75015 Paris, France.
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14533-8. doi: 10.1073/pnas.0800685105. Epub 2008 Sep 8.
There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile(146)-->Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlR(I146L)), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlR(I146L) in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future.
目前在人类中尚无已知的与催乳素（Prl）或其受体（PrlR）相关的遗传疾病。鉴于该激素系统在乳腺生理中的重要作用，我们推测Prl/PrlR基因的遗传异常可能与具有高增殖潜能的乳腺疾病的发生有关。多发性纤维腺瘤（MFA）是良性乳腺肿瘤，最常出现在年轻女性中，包括青春期，此时催乳素对乳腺具有公认的增殖作用。在一项涉及74例MFA患者和170例对照受试者的前瞻性研究中，我们发现4例患者在PrlR基因外显子6中存在杂合单核苷酸多态性，该突变导致其细胞外结构域编码的异亮氨酸（Ile）（146）被亮氨酸（Leu）取代。通过三种重组细胞模型（Ba/F3、HEK293和MCF-7细胞）评估，这一单一取代足以赋予受体变体（PrlR（I146L））组成型活性，具体表现为：（i）不依赖催乳素的PrlR酪氨酸磷酸化；（ii）信号转导子和转录激活子5（STAT5）信号通路的激活；（iii）对催乳素反应性报告基因的转录活性；（iv）细胞增殖和对细胞死亡的保护。患者乳腺样本中PrlR（I146L）的组成型活性通过增加的STAT5信号得到证实。这是对与人类疾病相关的PrlR功能突变的独特描述。组成型活性的特征均被一种特异性PrlR拮抗剂逆转，这为MFA或未来可能与该突变相关的任何其他疾病开辟了潜在的治疗途径。
