Targeting FACT complex suppresses mammary tumorigenesis in Her2/neu transgenic mice.
Development of safe and effective tumor-preventive treatments for high-risk patient populations and therapies for early-stage cancer remains a critical need in oncology. We have recently discovered compound with anticancer activity, Curaxin-137, which modulates several important signaling pathways involved in even the very early stages of cancer. In tumor cells, Curaxin-137 inhibits NF-κB- and HSF1-dependent transcription (prosurvival pathways) and activates p53 (a proapoptotic pathway) without inducing DNA damage. These effects result from chromatin trapping and inhibition of activity of the FACT (facilitates chromatin transcription) complex by Curaxin-137. FACT has not been previously implicated in cancer, but we found that its subunits are overexpressed in breast cancer. On the basis of this background, we tested whether Curaxin-137 could suppress tumorigenesis in MMTV-neu transgenic mice, which spontaneously develop mammary carcinoma due to steroid receptor-regulated expression of the Her2 proto-oncogene. We found that chronic administration of Curaxin-137 in a preventive regimen to MMTV-neu mice did not cause any detectable changes in normal organs and tissues, yet inhibited tumor onset, delayed tumor progression, and prolonged survival of mice in a dose-dependent manner. Curaxin-137 induced changes in FACT, altered NF-κB localization, and activated p53 in tumor cells as expected from its defined mechanism of action. These results support further investigation of Curaxin-137 as a potential preventive and/or early-stage therapeutic agent for breast cancer.
Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
Igor E
IE
Koman
Mairead
M
Commane
Geraldine
G
Paszkiewicz
Bhupinder
B
Hoonjan
Srabani
S
Pal
Alfiya
A
Safina
Ilya
I
Toshkov
Andrei A
AA
Purmal
Dan
D
Wang
Song
S
Liu
Carl
C
Morrison
Andrei V
AV
Gudkov
Katerina V
KV
Gurova
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D015996:Survival Rate; D035602:Transcriptional Elongation Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D035602:Transcriptional Elongation Factors; D016159:Tumor Suppressor Protein p53; C000715470:MAS1 protein, human; C073537:SSRP1 protein, human