Campbell Mallory C, Pontiggia Laura, Russell Ashley Y, Schwarting Roland, Camacho Jeanette, Jasmin Jean-Francois, Mercier Isabelle
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA 19104, USA.
Department of Mathematics, Physics and Statistics, Misher College of Arts and Sciences, University of the Sciences, Philadelphia, PA 19104, USA.
Oncotarget. 2018 Jul 13;9(54):30340-30354. doi: 10.18632/oncotarget.25719.
Breast cancers (BCas) that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are referred to as triple negative breast cancers (TNBCs) and have the poorest clinical outcome. Once these aggressive tumors progress to distant organs, the median survival decreases to 12 months. With endocrine therapies being ineffective in this BCa subtype, highly toxic chemo- and radiation therapies are the only options. A better understanding of the functional role(s) of molecular targets contributing to TNBC progression could help in the design and development of new treatments that are more targeted with less toxicity. CAPER (Co-activator of AP-1 and ER) is a nuclear transcriptional co-activator that was recently involved in ER-positive BCa progression, however its role in hormone-independent cancers remains unknown. Our current report demonstrates that CAPER expression is upregulated in human TNBC specimens compared to normal breast tissue and that its selective downregulation through a lentiviral-mediated shRNA knockdown approach resulted in decreased cell numbers in MDA-MB-231 and BT549 TNBC cell lines without affecting the growth of non-tumorigenic cell line MCF-10A. Concordant with these observations, CAPER knockdown was also associated with a decrease in DNA repair proteins leading to a marked increase in apoptosis, through caspase-3/7 activation without any changes in cell cycle. Collectively, we propose CAPER as an important signaling molecule in the development of TNBC linked to DNA repair mechanisms, which could lead to new therapeutic modalities for the treatment of this aggressive cancer.
缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）表达的乳腺癌（BCas）被称为三阴性乳腺癌（TNBCs），其临床预后最差。一旦这些侵袭性肿瘤进展至远处器官，中位生存期会降至12个月。由于内分泌疗法对这种乳腺癌亚型无效，高毒性的化疗和放疗是唯一的选择。更好地了解促成TNBC进展的分子靶点的功能作用，有助于设计和开发更具针对性、毒性更小的新疗法。CAPER（AP-1和ER的共激活因子）是一种核转录共激活因子，最近发现其与ER阳性乳腺癌的进展有关，但其在激素非依赖性癌症中的作用尚不清楚。我们目前的报告表明，与正常乳腺组织相比，人TNBC标本中CAPER的表达上调，并且通过慢病毒介导的shRNA敲低方法对其进行选择性下调，导致MDA-MB-231和BT549 TNBC细胞系中的细胞数量减少，而不影响非致瘤细胞系MCF-10A的生长。与这些观察结果一致，CAPER敲低还与DNA修复蛋白的减少有关，通过激活caspase- /7导致凋亡显著增加，而细胞周期没有任何变化。总体而言，我们提出CAPER是TNBC发展过程中与DNA修复机制相关的重要信号分子，这可能会为治疗这种侵袭性癌症带来新的治疗方式。
