Research Group in Molecular Oncology and Endocrinology, Department of Chemistry and Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, G9A 5H7 Canada.
Mol Cancer. 2011 Dec 14;10:148. doi: 10.1186/1476-4598-10-148.
Metastasis is the leading cause of death among breast cancer patients. Identifying key cellular factors controlling invasion and metastasis of breast cancer cells should pave the way to new therapeutic strategies efficiently interfering with the metastatic process. PAX2 (paired box 2) transcription factor is expressed by breast cancer cells in vivo and recently, it was shown to negatively regulate the expression of ERBB2 (erythroblastic leukemia viral oncogene homolog 2, HER-2/neu), a well-documented pro-invasive and pro-metastastic gene, in luminal/ERalpha-positive (ERα+) breast cancer cells. The objective of the present study was to investigate a putative role for PAX2 in the control of luminal breast cancer cells invasion, and to begin to characterize its regulation.
PAX2 activity was higher in cell lines from luminal compared to non-luminal subtype, and activation of PAX2 by estradiol was selectively achieved in breast cancer cell lines of the luminal subtype. This process was blocked by ICI 182780 and could be antagonized by IGF-1. Knockdown of PAX2 in luminal MCF-7 cells completely abrogated estradiol-induced downregulation of ERBB2 and decrease of cell invasion, whereas overexpression of PAX2 in these cells enhanced estradiol effects on ERBB2 levels and cell invasion.
The study demonstrates that PAX2 activation by estradiol is selectively achieved in breast cancer cells of the luminal subtype, via ERα, and identifies IGF-1 as a negative regulator of PAX2 activity in these cells. Further, it reveals a new role for PAX2 in the maintenance of a low invasive behavior in luminal breast cancer cells upon exposure to estradiol, and shows that overexpression and activation of PAX2 in these cells is sufficient to reduce their invasive ability.
转移是乳腺癌患者死亡的主要原因。确定控制乳腺癌细胞侵袭和转移的关键细胞因子，应该为新的治疗策略铺平道路，有效地干扰转移过程。PAX2（配对盒 2）转录因子在体内表达于乳腺癌细胞，最近有研究表明，其负调控 ERBB2（红细胞生成素样白血病病毒致癌基因同源物 2，HER-2/neu）的表达，而 ERBB2 是一个已被充分证明的促侵袭和促转移基因，在腔面/ERalpha 阳性（ERα+）乳腺癌细胞中。本研究的目的是研究 PAX2 在控制腔面乳腺癌细胞侵袭中的潜在作用，并开始对其调控进行特征描述。
PAX2 的活性在腔面细胞系中高于非腔面亚型，并且雌激素可以选择性地激活腔面亚型的乳腺癌细胞系中的 PAX2。这一过程被 ICI 182780 阻断，并可以被 IGF-1 拮抗。在腔面 MCF-7 细胞中敲低 PAX2 完全阻断了雌激素诱导的 ERBB2 下调和细胞侵袭减少，而在这些细胞中过表达 PAX2 则增强了雌激素对 ERBB2 水平和细胞侵袭的作用。
该研究表明，雌激素通过 ERα 选择性地激活腔面亚型的乳腺癌细胞中的 PAX2，并确定 IGF-1 是这些细胞中 PAX2 活性的负调节剂。此外，它揭示了 PAX2 在暴露于雌激素时维持腔面乳腺癌细胞低侵袭行为的新作用，并表明在这些细胞中过表达和激活 PAX2 足以降低其侵袭能力。
