Department of Medicine, Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Masonic Cancer Center, Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota.
Mol Cancer Res. 2018 Apr;16(4):707-719. doi: 10.1158/1541-7786.MCR-17-0598. Epub 2018 Jan 18.
Proline, glutamic acid, leucine-rich protein 1 (PELP1) is overexpressed in approximately 80% of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, interacting partners unique to cytoplasmic PELP1 and the mechanisms by which these interactions promote oncogenic PELP1 signaling were sought. AIB1 (amplified in breast cancer 1; also known as SRC-3 or NCOA3) was identified as a novel binding partner of cytoplasmic PELP1 in both estrogen receptor-positive (ER) and ER-negative cell lines. Cytoplasmic PELP1 expression elevated basal phosphorylation levels (i.e., activation) of AIB1 at Thr24, enhanced ALDH tumorsphere formation, and upregulated specific target genes independently of hormone stimulation. Direct manipulation of AIB1 levels using shRNA abrogated cytoplasmic PELP1-induced tumorsphere formation and downregulated cytoplasmic PELP1-specific target genes. SI-2, an AIB1 inhibitor, limited the PELP1/AIB1 interaction and decreased cytoplasmic PELP1-induced tumorsphere formation. Similar results were observed in a murine-derived MMTV-AIB1 tumor cell line. Furthermore, syngeneic tumor studies revealed that PELP1 knockdown resulted in increased survival of tumor-bearing mice as compared with mice injected with control cells. These data demonstrate that cytoplasmic PELP1/AIB1-containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression. .
脯氨酸、谷氨酸、亮氨酸丰富蛋白 1（PELP1）在大约 80%的浸润性乳腺癌肿瘤中过表达。PELP1 在核和细胞质之间动态穿梭，但在正常乳腺组织中主要位于核内。然而，PELP1 向细胞质的定位改变是一种致癌事件，可促进乳腺癌的发生和发展。在此，寻求与细胞质 PELP1 特异相互作用的伙伴以及这些相互作用促进致癌 PELP1 信号转导的机制。AIB1（乳腺癌扩增物 1；也称为 SRC-3 或 NCOA3）被鉴定为在雌激素受体阳性（ER）和 ER 阴性细胞系中细胞质 PELP1 的新结合伙伴。细胞质 PELP1 表达增加了 AIB1 在 Thr24 处的基础磷酸化水平（即激活），增强了 ALDH 肿瘤球形成，并独立于激素刺激上调特定靶基因。使用 shRNA 直接操纵 AIB1 水平可消除细胞质 PELP1 诱导的肿瘤球形成，并下调细胞质 PELP1 特异性靶基因。AIB1 抑制剂 SI-2 限制了 PELP1/AIB1 相互作用并减少了细胞质 PELP1 诱导的肿瘤球形成。在源自 MMTV-AIB1 的鼠源性肿瘤细胞系中观察到类似的结果。此外，同种异体肿瘤研究表明，与注射对照细胞的小鼠相比，PELP1 敲低导致荷瘤小鼠的存活率增加。这些数据表明，包含细胞质 PELP1/AIB1 的复合物可促进包括与雌激素无关的乳腺癌进展相关的干细胞样细胞生长在内的晚期癌症表型。
