Grible Jacqueline M, Zot Patricija, Olex Amy L, Hedrick Shannon E, Harrell J Chuck, Woock Alicia E, Idowu Michael O, Clevenger Charles V
Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
NPJ Breast Cancer. 2021 Mar 26;7(1):37. doi: 10.1038/s41523-021-00243-7.
The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. The goal of this study was to determine if a similar transforming event occurs with the hPRLr in human breast epithelial cells and to better understand the mechanism behind such transformation. hPRLrL+I co-expression in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism.
催乳素（PRL）及其受体（hPRLr）在乳腺癌发病机制中发挥着重要作用。中间型hPRLr（hPRLrI）是一种选择性剪接异构体，能够刺激细胞活力和增殖。最近发现，一种类似的截短型小鼠PRLr（mPRLr）与野生型mPRLr共表达时具有致癌性。本研究的目的是确定hPRLr在人乳腺上皮细胞中是否会发生类似的转化事件，并更好地理解这种转化背后的机制。在MCF10AT细胞中共表达hPRLrL + I会导致强大的体内和体外转化，而在MCF7细胞中敲低hPRLrI会显著降低体外恶性潜能。hPRLrL + I异二聚体比hPRLrL同二聚体表现出更高的稳定性，并且虽然能够激活Jak2、Ras和MAPK，但它们无法诱导Stat5a酪氨酸磷酸化。免疫组织化学乳腺癌组织微阵列数据和使用癌症基因组图谱（TCGA）的RNA测序分析均表明，较高的hPRLrI表达与三阴性乳腺癌相关。这些研究表明，hPRLrI与hPRLrL一起表达时，参与乳腺转化，并代表一种新的致癌机制。
