Merzoug-Larabi Messaouda, Youssef Ilige, Bui Ai Thu, Legay Christine, Loiodice Sophia, Lognon Sophie, Babajko Sylvie, Ricort Jean-Marc
Centre National de la Recherche Scientifique, CNRS UMR_8113, Laboratoire de Biologie et Pharmacologie Appliquée, Cachan, France.
École Normale Supérieure Paris-Saclay, Université Paris-Saclay, Cachan, France.
Front Pharmacol. 2020 Jan 31;10:1683. doi: 10.3389/fphar.2019.01683. eCollection 2019.
Exposure to bisphenol A (BPA), one of the most widespread endocrine disruptors present in our environment, has been associated with the recent increased prevalence and severity of several diseases such as diabetes, obesity, autism, reproductive and neurological defects, oral diseases, and cancers such as breast tumors. BPA is suspected to act through genomic and non-genomic pathways. However, its precise molecular mechanisms are still largely unknown. Our goal was to identify and characterize a new molecular target of BPA in breast cancer cells in order to better understand how this compound may affect breast tumor growth and development. By using (MCF-7, T47D, Hs578t, and MDA-MB231 cell lines) and models, we demonstrated that PKD1 is a functional non-genomic target of BPA. PKD1 specifically mediates BPA-induced cell proliferation, clonogenicity, and anchorage-independent growth of breast tumor cells. Additionally, low-doses of BPA (≤10 M) induced the phosphorylation of PKD1, a key signature of its activation state. Moreover, PKD1 overexpression increased the growth of BPA-exposed breast tumor xenografts in athymic female Swiss nude ( ) mice. These findings further our understanding of the molecular mechanisms of BPA. By defining PKD1 as a functional target of BPA in breast cancer cell proliferation and tumor development, they provide new insights into the pathogenesis related to the exposure to BPA and other endocrine disruptors acting similarly.
双酚A（BPA）是我们环境中存在的最普遍的内分泌干扰物之一，它与近期几种疾病的患病率和严重程度增加有关，如糖尿病、肥胖症、自闭症、生殖和神经缺陷、口腔疾病以及乳腺癌等癌症。双酚A被怀疑通过基因组和非基因组途径发挥作用。然而，其确切的分子机制在很大程度上仍然未知。我们的目标是在乳腺癌细胞中鉴定和表征双酚A的一个新的分子靶点，以便更好地了解这种化合物如何影响乳腺肿瘤的生长和发展。通过使用（MCF-7、T47D、Hs578t和MDA-MB231细胞系）和模型，我们证明蛋白激酶D1（PKD1）是双酚A的一个功能性非基因组靶点。PKD1特异性介导双酚A诱导的乳腺肿瘤细胞增殖、克隆形成能力和非锚定依赖性生长。此外，低剂量的双酚A（≤10μM）诱导PKD1的磷酸化，这是其激活状态的一个关键特征。此外，PKD1的过表达增加了在无胸腺雌性瑞士裸鼠中双酚A暴露的乳腺肿瘤异种移植瘤的生长。这些发现进一步加深了我们对双酚A分子机制的理解。通过将PKD1定义为双酚A在乳腺癌细胞增殖和肿瘤发展中的功能性靶点, 它们为与双酚A暴露及其他类似作用的内分泌干扰物相关的发病机制提供了新的见解。
