Department of Obstetrics and Gynecology and Cancer Therapy & Research Center, UT Health Science Center, San Antonio, TX 78229, USA.
Mol Cancer Res. 2012 Jan;10(1):25-33. doi: 10.1158/1541-7786.MCR-11-0456. Epub 2011 Nov 15.
Breast cancer metastasis is a major clinical problem. The molecular basis of breast cancer progression to metastasis remains poorly understood. PELP1 is an estrogen receptor (ER) coregulator that has been implicated as a proto-oncogene whose expression is deregulated in metastatic breast tumors and whose expression is retained in ER-negative tumors. We examined the mechanism and significance of PELP1-mediated signaling in ER-negative breast cancer progression using two ER-negative model cells (MDA-MB-231 and 4T1 cells) that stably express PELP1-shRNA. These model cells had reduced PELP1 expression (75% of endogenous levels) and exhibited less propensity to proliferate in growth assays in vitro. PELP1 downregulation substantially affected migration of ER-negative cells in Boyden chamber and invasion assays. Using mechanistic studies, we found that PELP1 modulated expression of several genes involved in the epithelial mesenchymal transition (EMT), including MMPs, SNAIL, TWIST, and ZEB. In addition, PELP1 knockdown reduced the in vivo metastatic potential of ER-negative breast cancer cells and significantly reduced lung metastatic nodules in a xenograft assay. These results implicate PELP1 as having a role in ER-negative breast cancer metastasis, reveal novel mechanism of coregulator regulation of metastasis via promoting cell motility/EMT by modulating expression of genes, and suggest PELP1 may be a potential therapeutic target for metastatic ER-negative breast cancer.
乳腺癌转移是一个主要的临床问题。乳腺癌进展为转移的分子基础仍知之甚少。PELP1 是一种雌激素受体 (ER) 共调节剂，被认为是一种原癌基因，其表达在转移性乳腺癌肿瘤中失调，而在 ER 阴性肿瘤中保留。我们使用两种稳定表达 PELP1-shRNA 的 ER 阴性模型细胞（MDA-MB-231 和 4T1 细胞）研究了 PELP1 介导的信号在 ER 阴性乳腺癌进展中的机制和意义。这些模型细胞的 PELP1 表达减少（内源性水平的 75%），并且在体外生长测定中增殖的倾向降低。PELP1 下调显著影响 ER 阴性细胞在 Boyden 室和侵袭测定中的迁移。通过机制研究，我们发现 PELP1 调节了几个参与上皮间质转化 (EMT) 的基因的表达，包括 MMPs、SNAIL、TWIST 和 ZEB。此外，PELP1 敲低降低了 ER 阴性乳腺癌细胞的体内转移潜力，并在异种移植测定中显著减少了肺转移结节。这些结果表明 PELP1 在 ER 阴性乳腺癌转移中起作用，揭示了共调节剂通过调节 EMT 中细胞迁移/基因表达来调节转移的新机制，并表明 PELP1 可能是转移性 ER 阴性乳腺癌的潜在治疗靶点。
