Delineation of Breast Cancer Cell Hierarchy Identifies the Subset Responsible for Dormancy

Overview

Journal Sci Rep

Specialty Science

Date 2012 Dec 4

PMID 23205268

Citations 41

Authors

Shyam A Patel

Shakti H Ramkissoon

Margarette Bryan

Lillian F Pliner

Gabriela Dontu

Prem S Patel

Sohrab Amiri

Sharon R Pine

Pranela Rameshwar

Affiliations

Soon will be listed here.

Abstract

The bone marrow (BM) is a major organ of breast cancer (BC) dormancy and a common source of BC resurgence. Gap junctional intercellular communication (GJIC) between BC cells (BCCs) and BM stroma facilitates dormancy. This study reports on a hierarchy of BCCs with the most immature subset (Oct4(hi)/CD44(hi/med)/CD24(-/+)) demonstrating chemoresistance, dormancy, and stem cell properties: self-renewal, serial passaging ability, cycling quiescence, long doubling time, asymmetric division, high metastatic and invasive capability. In vitro and in vivo studies indicated that this subset was responsible for GJIC with BM stroma. Similar BCCs were detected in the blood of patients despite aggressive treatment and in a patient with a relatively large tumor but no lymph node involvement. In brief, these findings identified a novel BCC subset with stem cell properties, with preference for dormancy and in the circulation of patients. The findings establish a working cellular hierarchy of BCCs based on phenotype and functions.

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References

Beltran A, Rivenbark A, Richardson B, Yuan X, Quian H, Hunt J . Generation of tumor-initiating cells by exogenous delivery of OCT4 transcription factor. Breast Cancer Res. 2011; 13(5):R94. PMC: 3262206. DOI: 10.1186/bcr3019. View

Kim R, Nam J . OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer. Lab Anim Res. 2011; 27(2):147-52. PMC: 3145994. DOI: 10.5625/lar.2011.27.2.147. View

Al-Hajj M, Wicha M, Benito-Hernandez A, Morrison S, Clarke M . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100(7):3983-8. PMC: 153034. DOI: 10.1073/pnas.0530291100. View

Gerrard L, Zhao D, Clark A, Cui W . Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotency. Stem Cells. 2004; 23(1):124-33. DOI: 10.1634/stemcells.2004-0102. View

McKnight J . Principles of chemotherapy. Clin Tech Small Anim Pract. 2003; 18(2):67-72. DOI: 10.1053/svms.2003.36617. View

Corcoran K, Trzaska K, Fernandes H, Bryan M, Taborga M, Srinivas V . Mesenchymal stem cells in early entry of breast cancer into bone marrow. PLoS One. 2008; 3(6):e2563. PMC: 2430536. DOI: 10.1371/journal.pone.0002563. View

Milsom M, Trumpp A . Bridging the information gap. Nat Immunol. 2011; 12(5):377-9. DOI: 10.1038/ni.2026. View

Kakarala M, Wicha M . Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol. 2008; 26(17):2813-20. PMC: 2789399. DOI: 10.1200/JCO.2008.16.3931. View

Hiraga T, Ito S, Nakamura H . Side population in MDA-MB-231 human breast cancer cells exhibits cancer stem cell-like properties without higher bone-metastatic potential. Oncol Rep. 2010; 25(1):289-96. View

10.

Kobayashi Y, Seino K, Hosonuma S, Ohara T, Itamochi H, Isonishi S . Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin. Gynecol Oncol. 2011; 121(2):390-4. DOI: 10.1016/j.ygyno.2010.12.366. View

11.

Liu S, Wicha M . Targeting breast cancer stem cells. J Clin Oncol. 2010; 28(25):4006-12. PMC: 4872314. DOI: 10.1200/JCO.2009.27.5388. View

12.

Wright M, Calcagno A, Salcido C, Carlson M, Ambudkar S, Varticovski L . Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008; 10(1):R10. PMC: 2374965. DOI: 10.1186/bcr1855. View

13.

Zhang W, Wang X, Xiao Z, Liu W, Chen B, Dai J . Mapping of the minimal internal ribosome entry site element in the human embryonic stem cell gene OCT4B mRNA. Biochem Biophys Res Commun. 2010; 394(3):750-4. DOI: 10.1016/j.bbrc.2010.03.064. View

14.

Rao G, Patel P, Idler S, Maloof P, Gascon P, Potian J . Facilitating role of preprotachykinin-I gene in the integration of breast cancer cells within the stromal compartment of the bone marrow: a model of early cancer progression. Cancer Res. 2004; 64(8):2874-81. DOI: 10.1158/0008-5472.can-03-3121. View

15.

Lim P, Bliss S, Patel S, Taborga M, Dave M, Gregory L . Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res. 2011; 71(5):1550-60. DOI: 10.1158/0008-5472.CAN-10-2372. View

16.

Wang X, Dai J . Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells. 2010; 28(5):885-93. PMC: 2962909. DOI: 10.1002/stem.419. View

17.

Liedtke S, Stephan M, Kogler G . Oct4 expression revisited: potential pitfalls for data misinterpretation in stem cell research. Biol Chem. 2008; 389(7):845-50. DOI: 10.1515/BC.2008.098. View

18.

King T, Fukushima L, Yasui Y, Lampe P, Bertram J . Inducible expression of the gap junction protein connexin43 decreases the neoplastic potential of HT-1080 human fibrosarcoma cells in vitro and in vivo. Mol Carcinog. 2002; 35(1):29-41. DOI: 10.1002/mc.10071. View

19.

Bodenstine T, Vaidya K, Ismail A, Beck B, Cook L, Diers A . Homotypic gap junctional communication associated with metastasis suppression increases with PKA activity and is unaffected by PI3K inhibition. Cancer Res. 2010; 70(23):10002-11. PMC: 3003438. DOI: 10.1158/0008-5472.CAN-10-2606. View

20.

Hu T, Liu S, Breiter D, Wang F, Tang Y, Sun S . Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 2008; 68(16):6533-40. DOI: 10.1158/0008-5472.CAN-07-6642. View