Breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor (PR), or hormonal epidermal growth factor receptor 2 (HER2) are referred to as triple negative breast cancer (TNBC) and have the poorest clinical outcome. Once these aggressive tumors progress to distant organs, the median survival of these patients is reduced to 12 months. With endocrine therapies being ineffective in this breast cancer subtype, highly toxic chemo- and radiation therapies becomes the only option. A better understanding of the functional role(s) of molecular targets inside TNBC would help in the design and development of new treatments that are more targeted with less toxicity. CAPER (Coactivator of AP-1 and ER) is an AP-1 coactivator that was recently involved in ER-positive breast cancer progression, however its role in hormone-independent cancers remains unknown. Our current report demonstrates that CAPER expression is upregulated in TNBC compared to normal breast tissue and its selective downregulation through a lentiviral-mediated shRNA knockdown approach resulted in a decreased adherent cell number in MDA-MB-231 and BT549 human TNBC cell lines. Concordant with this observation was the impairment of DNA damage pathways upon CAPER knockdown, leading to a marked increase in apoptosis. Clinically important was the observation that knockdown of CAPER significantly reduced the tumorigenicity of TNBC cells grown orthotopically in nude mice. Importantly, targeting CAPER expression in a non-tumorigenic breast cell line did not affect cell viability, suggesting a selectivity toward cancer cells. Collectively, we propose CAPER as an important signaling molecule associated with DNA repair in TNBC and these results could lead to further development of new therapeutic modalities for the treatment of TNBC.
|School:||University of the Sciences in Philadelphia|
|Department:||Pharmacology and Toxicology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 79/12(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmacology, Oncology|
|Keywords:||Breast cancer, Caper, Dna repair, Tnbc|
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