Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Cell Differentiation* ; Gene Knockdown Techniques*; Breast Neoplasms/*pathology ; Breast Neoplasms/*therapy ; Hyaluronan Receptors/*metabolism ; Neoplastic Stem Cells/*metabolism ; Neoplastic Stem Cells/*pathology; Animals ; Breast Neoplasms/genetics ; CD24 Antigen/metabolism ; Cell Cycle ; Cell Proliferation ; Cell Separation ; Cell Survival ; Cell Transformation, Neoplastic/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Neoplasm Metastasis/genetics ; RNA, Small Interfering/metabolism ; Tumor Cells, Cultured

Background: Breast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs).
Methods: We isolated a breast cancer cell population (CD44+CD24- cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44+CD24- phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs.
Results: Knockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs.
Conclusions: Knockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.

Int J Oncol. 2010 May;36(5):1309-14. (PMID: 20372807)
Oncogene. 2010 Sep 16;29(37):5204-13. (PMID: 20622894)
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5. (PMID: 19666588)
Endocrinology. 2006 Sep;147(9):4056-66. (PMID: 16809439)
Oncogene. 2007 Mar 15;26(12):1693-701. (PMID: 16983337)
Blood. 2007 Sep 15;110(6):1770-8. (PMID: 17507662)
J Clin Oncol. 2010 Sep 1;28(25):4006-12. (PMID: 20498387)
Development. 2004 Jun;131(12):2803-15. (PMID: 15142971)
Oncotarget. 2010 Nov;1(7):563-577. (PMID: 21317452)
Trends Cell Biol. 2006 Sep;16(9):467-76. (PMID: 16904320)
Future Oncol. 2011 Aug;7(8):995-1006. (PMID: 21823894)
PLoS Pathog. 2009 Oct;5(10):e1000617. (PMID: 19816567)
Nat Clin Pract Oncol. 2009 Feb;6(2):93-104. (PMID: 19107109)
Lipids. 2009 Jun;44(6):489-98. (PMID: 19381703)
J Genet Genomics. 2010 Jul;37(7):441-9. (PMID: 20659708)
Nature. 2004 Oct 7;431(7009):707-12. (PMID: 15361885)
Mol Cancer Res. 2009 Jul;7(7):989-99. (PMID: 19609002)
Breast Cancer Res. 2005;7(3):86-95. (PMID: 15987436)
Biochem Pharmacol. 2011 May 1;81(9):1124-35. (PMID: 21371442)
Breast Cancer Res Treat. 2011 Nov;130(2):387-98. (PMID: 21188630)
Onco Targets Ther. 2011;4:71-8. (PMID: 21792314)
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8. (PMID: 12629218)
Trends Parasitol. 2003 Jul;19(7):305-11. (PMID: 12855381)
PLoS One. 2008;3(10):e3469. (PMID: 18941626)
Mol Cancer Ther. 2010 May;9(5):1244-55. (PMID: 20423996)
J Dermatol Sci. 2010 Dec;60(3):187-92. (PMID: 21044828)
Breast Cancer Res. 2010;12(3):R31. (PMID: 20525204)
Epigenetics. 2011 Apr;6(4):428-39. (PMID: 21266853)
J Natl Cancer Inst. 2006 Jul 19;98(14):1011-4. (PMID: 16849684)
Anticancer Drugs. 2010 Nov;21(10):897-906. (PMID: 20838207)
Nat Rev Cancer. 2004 Jan;4(1):45-60. (PMID: 14681689)
Nat Rev Cancer. 2003 Dec;3(12):903-11. (PMID: 14737121)
Int J Hyperthermia. 2010;26(7):681-5. (PMID: 20653417)
J Mammary Gland Biol Neoplasia. 2001 Jul;6(3):339-53. (PMID: 11547902)
Breast Cancer Res Treat. 2009 Nov;118(1):113-24. (PMID: 19415485)
Eur J Cancer. 1999 May;35(5):711-3. (PMID: 10505029)
Semin Oncol. 2003 Oct;30(5 Suppl 16):133-42. (PMID: 14613034)
Cancer Sci. 2010 Aug;101(8):1861-5. (PMID: 20491775)
Expert Opin Ther Targets. 2009 Apr;13(4):469-78. (PMID: 19335068)
Oncogene. 2011 Mar 24;30(12):1449-59. (PMID: 21102519)
J Cell Biol. 2000 Feb 7;148(3):567-78. (PMID: 10662781)
Cancer Cell. 2005 Feb;7(2):167-78. (PMID: 15710329)
J Clin Invest. 2007 Aug;117(8):2051-8. (PMID: 17671639)
J Biol Chem. 1997 May 9;272(19):12492-4. (PMID: 9139698)
Hum Pathol. 2009 Nov;40(11):1517-27. (PMID: 19716155)
Mol Cancer Res. 2006 Nov;4(11):873-83. (PMID: 17114345)
Breast Cancer Res. 2008;10(1):R10. (PMID: 18241344)
J Control Release. 2011 Feb 10;149(3):281-91. (PMID: 20971141)
Cancer Res. 2005 Jul 1;65(13):5506-11. (PMID: 15994920)
Nat Biotechnol. 2006 Jun;24(6):687-96. (PMID: 16732270)
Int J Cancer. 2000 Jun 1;86(5):652-9. (PMID: 10797286)
Oncogene. 2004 Oct 21;23(49):8049-64. (PMID: 15377997)
J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):79-82. (PMID: 19259795)
Cancer Cell. 2004 Aug;6(2):117-27. (PMID: 15324695)
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5774-9. (PMID: 18391223)
Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):618-23. (PMID: 17202265)
Nat Rev Clin Oncol. 2011 Feb;8(2):97-106. (PMID: 21151206)
Cell Cycle. 2009 Oct 15;8(20):3297-302. (PMID: 19806016)
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Feb;5(1):3-14. (PMID: 15720220)
Br J Cancer. 2004 Jun 14;90(12):2344-8. (PMID: 15150568)
Oncogene. 2008 Oct 16;27(47):6120-30. (PMID: 18591932)

0 (CD24 Antigen)
0 (Hyaluronan Receptors)
0 (RNA, Small Interfering)

Date Created: 20111214 Date Completed: 20120315 Latest Revision: 20211021

20231215

PMC3251542

10.1186/1479-5876-9-209

22152097