乳腺癌干細(xì)胞是乳腺癌細(xì)胞中一類具有自我更新能力和多向分化潛能的細(xì)胞，具有高度的致瘤性和侵襲轉(zhuǎn)移性，在乳腺癌的轉(zhuǎn)移和復(fù)發(fā)以及放化療抵抗中都起著重要作用。針對(duì)乳腺癌干細(xì)胞進(jìn)行靶向治療對(duì)提高乳腺癌療效具有重要意義。
2016年4月5日，美國癌癥研究協(xié)會(huì)（AACR）官方期刊《癌癥研究》在線發(fā)表了美國奧古斯塔大學(xué)、德克薩斯理工大學(xué)的研究報(bào)告，發(fā)現(xiàn)兩種現(xiàn)有化療藥物聯(lián)合使用能夠有效針對(duì)乳腺癌干細(xì)胞，而單獨(dú)使用效果不佳。
這兩種藥物分別是5-阿扎胞苷和HDAC抑制劑丁酸鹽，將這兩種藥物聯(lián)合使用能夠減少乳腺癌小鼠模型的癌癥干細(xì)胞數(shù)目，并改善生存率。
目前多數(shù)化療藥物都不能殺死癌癥干細(xì)胞，而癌癥干細(xì)胞是癌細(xì)胞的來源，同時(shí)也是癌癥復(fù)發(fā)轉(zhuǎn)移的重要原因，因此這種藥物聯(lián)合方式可能適用于所有乳腺癌患者。
該研究證實(shí)這兩種藥物能夠直接影響癌癥干細(xì)胞內(nèi)參與分化形成癌細(xì)胞的至少兩條信號(hào)通路，使異常的基因表達(dá)正?；钄啻侔┘?xì)胞生長信號(hào)。這兩種藥物之前主要用于增強(qiáng)雌激素受體陽性乳腺癌治療藥物——他莫西芬的作用效果，他莫西芬能夠通過阻斷雌激素受體治療乳腺癌，而添加另外兩種藥物能夠幫助降低乳腺癌復(fù)發(fā)率。
5-阿扎胞苷是DNMT1的抑制劑，2015年4月24日發(fā)表在《自然·通訊》雜志的研究中發(fā)現(xiàn)DNMT1對(duì)于維持正常乳腺干細(xì)胞以及癌癥干細(xì)胞都非常重要，并且DNMT1在乳腺癌干細(xì)胞中表達(dá)比正常乳腺干細(xì)胞更高。抑制乳腺癌模型中DNMT1的表達(dá)能夠消除大約80%的腫瘤，特別是侵襲性腫瘤。
除此之外，RAD51AP1以及SPC25這兩種信號(hào)分子也在乳腺癌干細(xì)胞中存在高表達(dá)，在正常細(xì)胞中，這兩種分子能夠幫助修復(fù)DNA損傷，但在癌細(xì)胞中可以促進(jìn)癌細(xì)胞的生長和轉(zhuǎn)移。丁酸鹽能夠阻斷這兩種分子的作用進(jìn)而抑制癌細(xì)胞生長。
該研究從干細(xì)胞水平為徹底“根”治乳腺癌提供了新的治療方向。
Cancer Res. 2016 Apr 5. [Epub ahead of print]
Combined inhibition of DNMT and HDAC blocks the tumorigenicity of cancer stem-like cells and attenuates mammary tumor growth.
Rajneesh Pathania, Sabarish Ramachandran, Gurusamy Mariappan, Priyanka Thakur, Huidong Shi, Jeong-Hyeon Choi, Santhakumar Manicassamy, Ravindra Kolhe, Puttur D Prasad, Suash Sharma, Bal L Lokeshwar, Vadivel Ganapathy, Muthusamy Thangaraju.
Augusta University; Texas Tech University Health Sciences Center.
Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSCs), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Further, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer.
DOI: 10.1158/0008-5472.CAN-15-2249
Nat Commun. 2015 Apr 24;6:6910.
DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis.
Pathania R, Ramachandran S, Elangovan S, Padia R, Yang P, Cinghu S, Veeranan-Karmegam R, Arjunan P, Gnana-Prakasam JP, Sadanand F, Pei L, Chang CS, Choi JH, Shi H, Manicassamy S, Prasad PD, Sharma S, Ganapathy V, Jothi R, Thangaraju M.
Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.
PMID: 25908435
PMCID: PMC4410389
DOI: 10.1038/ncomms7910
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