Courtney M. Edwards, Jeremy F. Kane, Jailyn A. Smith, Déja M. Grant, Jasmine A. Johnson, Maria A. Hernandez Diaz, Lawrence A. Vecchi, Kai M. Bracey, Tolu N. Omokehinde, Joseph R. Fontana, Breelyn A. Karno, Halee T. Scott, Carolina J. Vogel, Jonathan W. Lowery, T. John Martin, Rachelle W. Johnson
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引用次数: 0
摘要
甲状旁腺激素(PTH)相关蛋白(PTHrP)在乳腺癌中的作用仍存在争议,临床前研究中有报道称 PTHrP 可抑制或促进原发性肿瘤生长。在这里,我们通过稳定表达 PTHrP(-36-139aa)或单独缺失核定位序列(NLS)的截断形式或结合 C 端,评估 PTHrP 的特定生物结构域在肿瘤进展中的作用,从而深入了解这些相互矛盾的研究结果。虽然全长 PTHrP 分子(-36-139aa)不会改变肿瘤的发生,但单独缺失 NLS 的 PTHrP 会通过下调 p27 来加速原发性肿瘤的生长,而缺失 NLS 和 C 端的 PTHrP 则会通过肿瘤抑制因子白血病抑制因子受体(LIFR)的 p27 诱导来抑制肿瘤的生长。缺乏 NLS 和 C 端的 PTHrP 对 p27 的诱导作用在骨播散细胞中持续存在,但并不能阻止转移生长,这与原发肿瘤部位形成鲜明对比。这些数据表明,PTHrP NLS 起着肿瘤抑制剂的作用,而 PTHrP C 端可能起着致癌开关的作用,通过对 p27 信号的不同调控来促进肿瘤的进展。
PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR
The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.
期刊介绍:
Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.