Are breast cancer stem cells the key to resolving clinical issues in breast cancer therapy?
Review Article

Are breast cancer stem cells the key to resolving clinical issues in breast cancer therapy?

Hidetaka Shima1, Akimitsu Yamada1, Takashi Ishikawa2, Itaru Endo1

1Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan; 2Department of Breast disease, Tokyo Medical University Hospital, Tokyo 160-0023, Japan

Contributions: (I) Conception and design: All authors; (II) Administrative support: A Yamada, T Ishikawa, I Endo; (III) Provision of study materials or patients: A Yamada, T Ishikawa, I Endo; (IV) Collection and assembly of data: H Shima; (V) Data analysis and interpretation: H Shima, A Yamada; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Akimitsu Yamada. Department of Gastroenterological Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa 236-0004, Japan. Email: yakimitsu@gmail.com.

Abstract: Despite the dramatic advances in breast cancer treatment over the past two decades, it is still the most common malignancies in women. One of the reasons patients succumb to breast cancer is treatment resistance leading to metastasis and recurrence. Recently, cancer stem cells (CSCs) have been suggested as a cause of metastasis and recurrence in several cancers because of their unique characteristics, including self-renewal, pluripotency, and high proliferative ability. Increasing evidence has implicated breast cancer stem cells (BCSCs) as essential for tumor development, progression, recurrence, and treatment resistance. BCSCs exhibit resistance to treatment owing to several inter-related factors, including overexpression of ATP-binding cassette (ABC) transporters and increased aldehyde dehydrogenase (ALDH) activity, DNA repair, and reactive oxygen species (ROS) scavenging. In addition, the Notch, Hedgehog, and Wnt signaling pathways have been suggested as the major pathways involved in the self-renewal and differentiation of BCSCs. Despite growing evidence suggesting the importance of BCSCs in progression and metastasis, clear criteria for the identification of BCSCs in clinical practice have yet to be established. Several potential markers have been suggested, including CD44+/CD24−/low, ALDH1, EpCAM/ESA, and nestin; however, there is no standard method to detect BCSCs. Triple-negative breast cancer, which shows initial chemosensitivity, demonstrates worsened prognosis due to therapy resistance, which might be related to the presence of BCSCs. Several clinical trials aimed at the identification of BCSCs or the development of BCSC-targeted therapy are in progress. Determining the clinical relevance of BCSCs may provide clues for overcoming therapy resistance in breast cancer.

Keywords: Breast cancer; cancer stem cell (CSC); therapy resistance; aldehyde dehydrogenase 1 (ALDH1)


Submitted Jun 16, 2016. Accepted for publication Jun 28, 2016.

doi: 10.21037/gs.2016.08.03


Introduction

Breast cancer is the most common malignancy in women in most of the world (1). Despite recent improvement in the 5-year survival rate due to treatment advances, more than 40,000 women in the US die from breast cancer every year. For many malignancies, cancer stem cells (CSCs) have been implicated in the metastasis and recurrence due to treatment resistance (2). CSCs are a small population of cells in the tumor that have unique characteristics, such as self-renewal and the ability to generate heterogenic lineages of cancer cells (3). These characteristics make CSCs a likely source of tumor initiation, heterogeneity, progression, metastasis, and recurrence (4). In numerous solid tumors, including those in brain, pancreatic, ovarian, and breast cancers, CSCs show resistance to chemotherapy and radiotherapy. Furthermore, CSCs exhibit characteristics of epithelial-to-mesenchymal-transition (EMT), a known mechanism of metastasis (5). Although several biomarkers have been developed for CSCs, CSC characterization is not currently part of standard clinical practice. In this review, we will discuss our current understanding of the characteristics and biomarkers of CSCs in breast cancer and describe H19, a new novel potential biomarker of breast cancer stem cells (BCSCs).


BCSCs

The origin and characteristics of BCSCs

Modern stem cell theory was developed from studies on hematological malignancies in the 1960s, and BCSCs were first isolated from solid tumors in 2003. The tumorigenicity of BCSCs was suggested by their phenotype: CD44+CD24low/− and lack of lineage markers, such as CD2, CD3, CD10, CD16, CD18, CD31, CD64, and CD104b (6). Several theories have been proposed for the origin of BCSCs, including improper regulation or mutations that may lead to the transformation of dormant normal stem cells into BCSCs (7), de novo misplacement of somatic stem cells (8), and intratumoral lineages differentiated from common progenitor cells (9).

Common BCSC characteristics have been reported in several studies. BCSCs have the ability for self-renewal and high proliferation and are able to generate heterogenic lineages of cancer cells, so called “pluripotency.” These BCSC characteristics are recognized as one of the reasons for treatment failure.

Therapy resistance

Treatment modalities for breast cancer include surgery, chemotherapy, endocrine therapy, and radiotherapy. One of the clinical problems with BCSCs is their resistance to current chemotherapy, endocrine therapy, and radiotherapy. There are four major mechanisms that lead to treatment resistance in BCSCs: overexpression of ATP-binding cassette (ABC) transporters, increased aldehyde dehydrogenase (ALDH) activity, increased DNA repair, and elevated reactive oxygen species (ROS) scavenging.

ABC transporters are transmembrane proteins that can pump various compounds and small molecules from the cell. These transporters are considered important in multidrug resistance in various cancers (10). Among the 49 known ABC transporters, ABCB1 [P-glycoprotein (PgP), multidrug resistance protein 1 (MDR1)], ABCC1 [multidrug resistance-associated protein 1 (MRP1)], and ABCG2 [breast cancer resistance protein (BCRP)] have been shown to be related to multidrug resistance in breast cancer, because these transporters pump out anthracycline or taxans, two key drugs for breast cancer treatment (11). Furthermore, Jonker et al. demonstrated that ABCB1 and ABCG2 contribute to the stem cell phenotype in normal murine mammary glands (12). Britton et al. demonstrated that the CSCs present in breast cancer cell lines show increased expression of ABCG2 and increased drug resistance (13,14). These results suggest the important role of ABCB1 and ABCG2 in BCSCs.

ALDH is a family of enzymes involved in the oxidation of intracellular aldehydes to carboxylic acids and retinoic acid and in γ-amino butyric acid biosynthesis, and ALDH plays a significant role in the survival and differentiation of BCSCs (15,16). ALDH induces radioresistance in BCSCs both through direct removal of oxygen radicals and indirect production of the antioxidant compound nicotinamide adenine dinucleotide (phosphate) (17). ALDH1 is also associated with breast cancer malignancy, metastasis, and invasion (18). We reported that ALDH1 expression in breast cancer is related to aggressive phenotypes and poor prognosis (19). ALDH1-positive tumors exhibit paclitaxel and epirubicin resistance, and the population of ALDH1-positive cells was shown to increase after chemotherapy (20).

Increased DNA repair is another mechanism of therapy resistance. Radiation and several chemotherapy drugs damage DNA by inhibiting DNA synthesis or topoisomerase activity, or by promoting the formation of DNA crosslinks. Double strand breaks are the most lethal type of DNA damage, which is critical for cancer cells. DNA repair failure usually results in cell death (21); however, BCSCs can repair this lethal type of DNA damage two ways, through homologous recombination (HR) or non-homologous end-joining (NHEJ). HR is similar to chromosomal crossover during meiosis; it requires the presence of a nearly identical sequence, and sister chromatids are used as a template for repair of the break. Although HR can be used as a repair mechanism only during S to G2 phase after DNA replication, (owing to the requirement for a sister chromatid), HR introduces fewer errors than NHEJ. However, in NHEJ, the ends of a double-strand break are directly ligated without the need for a homologous template, and repair via NHEJ can occur in G1 phase; however, it is associated with increased errors compared to HR (22).

ROS are chemically reactive molecules containing oxygen that are formed as a natural byproduct of normal oxygen metabolism. At normal levels, ROS participate in the regulation of various physiological events, such as cell proliferation, cell migration, wound healing, and angiogenesis (22). However, excess ROS produced in response to environmental stresses, such as radiation, UV, or heat exposure, interact with cell components, such as DNA, proteins, and lipids, which typically induces cell death (23). However, CSCs have specific mechanisms to guard against the genotoxic effects of ROS, including effective ROS scavenging and lower levels of ROS production. In addition, the genes encoding superoxide dismutase, catalase, and glutathione peroxidase, all of which are involved in ROS scavenging, are significantly upregulated in BCSCs (24). These four mechanisms of therapy resistance in BCSCs are correlated with each other.

Identification of BCSC markers

BCSCs were first identified and isolated according to their CD44+/CD24−/low Lin phenotype in 2003 (6). Since then, the CD44+/CD24 phenotype has been used as a reliable phenotype for the isolation of BCSCs (25-27). CD44 is a transmembrane glycoprotein that binds to many extracellular matrix proteins, of which hyaluronic acid is the most common. Hyaluronic acid is a key element for cell adhesion, motion, migration, proliferation, invasion, and angiogenesis (28), and its interaction with osteopontin leads to tumor progression (29). In contrast, the absence of CD24, another small surface glycoprotein, enhances tumor growth and metastasis (30). Higher levels of CD44 mRNA and protein expression were observed in the basal subtype of breast cancer, which has a poor clinical outcome (31). Patients with tumors overexpressing CD44 have significantly worse overall survival. Whole genome analysis revealed that CD44 expression was enriched in basal-type breast cancer and was correlated with EMT and CSC gene profiles (31). Another recent study showed that CD44 expression was elevated in tumor-initiating cells in many cancers (32). Thus, CD44 is thought to be a biomarker for CSCs (33). Subsequent functional studies have shown that CD44 is involved in tumorigenesis and metastasis in breast cancers (34-36) and many other cancers, such as colon (37-39), bladder (40), and gastric (41) cancer.

As mentioned above, ALDH is a recognized BCSC marker (42). ALDH is a family of cytosolic enzymes that oxidizes intracellular aldehydes and retinol during the differentiation of rudimentary stem cells (43). ALDH1, which is the dominant enzyme in mammals, mediates the conversion of retinaldehyde to retinoic acid (44). Similar to CD44, ALDH1 expression and activity is increased in normal tissue and in many malignancies. ALDH1 also appears to have increased activity in BCSC populations (45).

Intriguingly, studies have suggested that the ALDH1-active cell population only slightly overlaps with the CD44+CD24low/− BCSC population. Although the population of ALDH1-active, CD44+CD24low/− cells was very small, tumorigenic capacity of this population was highly enriched (42).

Other markers that have been used to identify BCSCs include EpCAM/ESA, nestin, ganglioside GD2, CD133 (prominin-1), CD61/β3 integrin, CD24hi/CD49Fhi/DNERhi, CD24+CD29+, Sca1, CD44+ CD49fhi CD133/2hi, CD49f and CD61, CXCR4, CXCL1, and HMGCS (26,46-49).

Several clinical trials have aimed to characterize BCSCs in both healthy populations and breast cancer patients (45), which have improved our understanding of BCSC markers. However, there are no standard criteria to identify BCSCs in human breast cancer.

H19 gene as a possible BCSC marker

H19 is a genomic imprinted oncofetal gene localized on human chromosome 11p15.5, and its oncogenic role was recently recognized as cancer stemness. H19 is only expressed from maternal alleles without a protein product, and it accumulates in the human placenta, several fetal tissues, and adult organs, including the mammary gland (50-53). Aberrant expression of H19 has been observed in breast cancer as well as numerous other solid tumors. Although the number of studies on H19 is increasing, the role of H19 remains controversial (51,54). Hao et al. reported that overexpression of H19 lowered the tumorigenic properties of cells, which demonstrates the tumor suppressor activity of H19 (55). Conversely, several studies have suggested its tumorigenic role in many cancers, including breast cancer (56-63). A relationship between H19 and cancer stemness has also been suggested. In many cancers, increased expression of H19 correlates with overexpression of stem cell surface markers (CD44, CD166, and TROP2) and pluripotency transcription factors (Oct4 and Sox2), enhanced sphere-forming capacity, high cellular proliferation, and a high rate of apoptosis (57,61-63). Thus, H19 has been suggested as a possible marker of BCSCs.

BCSCs and breast cancer molecular subtypes

Breast cancers have been classified into five major molecular subtypes, based on gene-expression profiling data: luminal A, luminal B, human epidermal growth factor 2 (HER2) overexpressing, basal like, and claudin low (64-66). Although these molecular subtypes are not currently used in most clinical settings, owing to the difficulty of use, certain immunohistochemical features can be used to predict these molecular subtypes.

The luminal-A subtype is the most common, and it is characterized by low-grade histological features, positive estrogen receptor (ER) expression, and no HER2 expression. The luminal-B subtype is similar to luminal-A, but has a higher proliferation index and worse prognosis. HER2-overexpressing cancers have a higher histological grade and worse prognosis that has improved dramatically with HER2-targeted therapies. The basal-like subtype is nearly equivalent to immunohistochemical triple-negative breast cancer (TNBC) in that it lacks ER, progesterone receptor (PR), and HER2 expression, and has a poor clinical outcome (67-70). The claudin-low subtype is characterized by decreased expression of genes related to tight junctions and cell-to-cell adhesion. However, it lacks distinct histological features; therefore, it cannot be identified by immunohistochemical methods (64,71).

These subtypes differ not only in their rates of relapse, metastasis, and response to therapies, but also in the proportion of BCSCs. CD44+/CD24−/low BCSCs are generally enriched in undifferentiated subtypes, such as claudin-low, basal-like, and HER2-overexpressing subtypes. ALDH1+ BCSCs have a similarly enriched distribution in basal-like and HER2-overexpressing subtypes. Enrichment of stem-like and mesenchymal signatures in the claudin-low subtype was demonstrated by examining gene expression profiles, and such enrichment might enable EMT. This BCSC-like population might cause therapy resistance in breast cancer.


Future directions

Although our understanding of BCSCs has increased dramatically in recent years, we need to translate these basic findings to the clinical setting. BCSCs can explain the existence of a small population of cancer cells in human breast cancer with high therapy resistance, resulting in poor prognosis. Despite initial chemosensitivity, patients with basal-like subtype have a worse prognosis. This paradoxical characteristic of the basal-like subtype might be because of the presence of BCSCs in the tumor that remain after chemotherapy, causing a higher likelihood of relapse. Identification of BCSCs in breast cancer and the development of BCSC-targeted therapies have the potential to improve survival and quality of life of cancer patients.

Actually, several molecular-targeted therapies against BCSCs have already been developed. The Notch, Hedgehog, and Wnt pathways have been suggested as the major pathways in BCSCs (22,72). Dysregulation of the Notch and Hedgehog pathways, which are involved in normal stem cell self-renewal and differentiation, results in a BCSC phenotype in breast cancer (73). The Wnt pathway plays a pivotal role in stem cell self-renewal and preservation of an undifferentiated state (74). However, these pathways also regulate essential functions in normal tissues and stem cells. Since specificity is the key to developing targeted therapies, they are not ideal targets. Several anti-BCSCs drugs targeting these pathways have been developed and enrolled in clinical trials (45). Determining the clinical relevance of BCSCs will give us clues about how to overcome therapy resistance in breast cancer.


Acknowledgements

Funding: This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (Grant Number 16K19055 for Akimitsu Yamada).


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30. [Crossref] [PubMed]
  2. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-11. [Crossref] [PubMed]
  3. Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006;66:9339-44. [Crossref] [PubMed]
  4. Wang H, Zhang Y, Du Y. Ovarian and breast cancer spheres are similar in transcriptomic features and sensitive to fenretinide. Biomed Res Int 2013;2013:510905.
  5. Lehmann C, Jobs G, Thomas M, et al. Established breast cancer stem cell markers do not correlate with in vivo tumorigenicity of tumor-initiating cells. Int J Oncol 2012;41:1932-42. [PubMed]
  6. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983-8. [Crossref] [PubMed]
  7. Hartwig FP, Nedel F, Collares T, et al. Oncogenic somatic events in tissue-specific stem cells: a role in cancer recurrence? Ageing Res Rev 2014;13:100-6. [Crossref] [PubMed]
  8. Wang RA, Li ZS, Zhang HZ, et al. Invasive cancers are not necessarily from preformed in situ tumours - an alternative way of carcinogenesis from misplaced stem cells. J Cell Mol Med 2013;17:921-6. [Crossref] [PubMed]
  9. Gorden BH, Kim JH, Sarver AL, et al. dentification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization. Am J Pathol 2014;184:985-95. [Crossref] [PubMed]
  10. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48-58. [Crossref] [PubMed]
  11. Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics 2009;3:281-90. [Crossref] [PubMed]
  12. Jonker JW, Freeman J, Bolscher E, et al. Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 2005;23:1059-65. [Crossref] [PubMed]
  13. Britton KM, Eyre R, Harvey IJ, et al. Breast cancer, side population cells and ABCG2 expression. Cancer Lett 2012;323:97-105. [Crossref] [PubMed]
  14. Britton KM, Kirby JA, Lennard TW, et al. Cancer stem cells and side population cells in breast cancer and metastasis. Cancers (Basel) 2011;3:2106-30. [Crossref] [PubMed]
  15. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 2011;7:292-306. [Crossref] [PubMed]
  16. Young SZ, Bordey A. GABA's control of stem and cancer cell proliferation in adult neural and peripheral niches. Physiology (Bethesda) 2009;24:171-85. [Crossref] [PubMed]
  17. Singh S, Brocker C, Koppaka V, et al. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med 2013;56:89-101. [Crossref] [PubMed]
  18. Croker AK, Goodale D, Chu J, et al. High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 2009;13:2236-52. [Crossref] [PubMed]
  19. Kida K, Ishikawa T, Yamada A, et al. Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype. Breast Cancer Res Treat 2016;156:261-9. [Crossref] [PubMed]
  20. Tanei T, Morimoto K, Shimazu K, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 2009;15:4234-41. [Crossref] [PubMed]
  21. Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol 2013;20:648-59. [Crossref] [PubMed]
  22. Peitzsch C, Kurth I, Kunz-Schughart L, et al. Discovery of the cancer stem cell related determinants of radioresistance. Radiother Oncol 2013;108:378-87. [Crossref] [PubMed]
  23. Cook JA, Gius D, Wink DA, et al. Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol 2004;14:259-66. [Crossref] [PubMed]
  24. Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009;458:780-3. [Crossref] [PubMed]
  25. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005;65:5506-11. [Crossref] [PubMed]
  26. Wright MH, Calcagno AM, Salcido CD, et al. Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 2008;10:R10. [Crossref] [PubMed]
  27. Perrone G, Gaeta LM, Zagami M, et al. In situ identification of CD44+/CD24- cancer cells in primary human breast carcinomas. PLoS One 2012;7:e43110. [Crossref] [PubMed]
  28. Herrera-Gayol A, Jothy S. Adhesion proteins in the biology of breast cancer: contribution of CD44. Exp Mol Pathol 1999;66:149-56. [Crossref] [PubMed]
  29. Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol 2006;16:79-87. [Crossref] [PubMed]
  30. Schabath H, Runz S, Joumaa S, et al. CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. J Cell Sci 2006;119:314-25. [Crossref] [PubMed]
  31. Xu H, Tian Y, Yuan X, et al. Enrichment of CD44 in basal-type breast cancer correlates with EMT, cancer stem cell gene profile, and prognosis. Onco Targets Ther 2016;9:431-44. [PubMed]
  32. Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 2011;11:254-67. [Crossref] [PubMed]
  33. Basakran NS. CD44 as a potential diagnostic tumor marker. Saudi Med J 2015;36:273-9. [Crossref] [PubMed]
  34. Xie G, Yao Q, Liu Y, et al. IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures. Int J Oncol 2012;40:1171-9. [PubMed]
  35. Uchino M, Kojima H, Wada K, et al. Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. BMC Cancer 2010;10:414. [Crossref] [PubMed]
  36. Cho Y, Lee HW, Kang HG, et al. Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer. Oncotarget 2015;6:8709-21. [Crossref] [PubMed]
  37. Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007;104:10158-63. [Crossref] [PubMed]
  38. Du L, Wang H, He L, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res 2008;14:6751-60. [Crossref] [PubMed]
  39. Santoyo-Ramos P, Likhatcheva M, García-Zepeda EA, et al. Hypoxia-inducible factors modulate the stemness and malignancy of colon cancer cells by playing opposite roles in canonical Wnt signaling. PLoS One 2014;9:e112580. [Crossref] [PubMed]
  40. Wu K, Ning Z, Zeng J, et al. Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness. Cell Signal 2013;25:2625-33. [Crossref] [PubMed]
  41. Yu D, Shin HS, Lee YS, et al. miR-106b modulates cancer stem cell characteristics through TGF-β/Smad signaling in CD44-positive gastric cancer cells. Lab Invest 2014;94:1370-81. [Crossref] [PubMed]
  42. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1:555-67. [Crossref] [PubMed]
  43. Balicki D. Moving forward in human mammary stem cell biology and breast cancer prognostication using ALDH1. Cell Stem Cell 2007;1:485-7. [Crossref] [PubMed]
  44. Chute JP, Muramoto GG, Whitesides J, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A 2006;103:11707-12. [Crossref] [PubMed]
  45. Lin CY, Barry-Holson KQ, Allison KH. Breast cancer stem cells: are we ready to go from bench to bedside? Histopathology 2016;68:119-37. [Crossref] [PubMed]
  46. Lee WJ, Kim SC, Yoon JH, et al. Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set and Network Analysis. PLoS One 2016;11:e0148818. [Crossref] [PubMed]
  47. Vaillant F, Asselin-Labat ML, Shackleton M, et al. The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res 2008;68:7711-7. [Crossref] [PubMed]
  48. Cariati M, Naderi A, Brown JP, et al. Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer 2008;122:298-304. [Crossref] [PubMed]
  49. Meyer MJ, Fleming JM, Lin AF, et al. CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res 2010;70:4624-33. [Crossref] [PubMed]
  50. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer 2011;10:38. [Crossref] [PubMed]
  51. Matouk IJ, DeGroot N, Mezan S, et al. The H19 non-coding RNA is essential for human tumor growth. PLoS One 2007;2:e845. [Crossref] [PubMed]
  52. Poirier F, Chan CT, Timmons PM, et al. The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo. Development 1991;113:1105-14. [PubMed]
  53. Pachnis V, Brannan CI, Tilghman SM. The structure and expression of a novel gene activated in early mouse embryogenesis. EMBO J 1988;7:673-81. [PubMed]
  54. Yoshimizu T, Miroglio A, Ripoche MA, et al. The H19 locus acts in vivo as a tumor suppressor. Proc Natl Acad Sci U S A 2008;105:12417-22. [Crossref] [PubMed]
  55. Hao Y, Crenshaw T, Moulton T, et al. Tumour-suppressor activity of H19 RNA. Nature 1993;365:764-7. [Crossref] [PubMed]
  56. Lottin S, Adriaenssens E, Dupressoir T, et al. Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. Carcinogenesis 2002;23:1885-95. [Crossref] [PubMed]
  57. Zeira E, Abramovitch R, Meir K, et al. The knockdown of H19lncRNA reveals its regulatory role in pluripotency and tumorigenesis of human embryonic carcinoma cells. Oncotarget 2015;6:34691-703. [PubMed]
  58. Chen JS, Wang YF, Zhang XQ, et al. H19 serves as a diagnostic biomarker and up-regulation of H19 expression contributes to poor prognosis in patients with gastric cancer. Neoplasma 2016;63:223-30. [PubMed]
  59. Yu LL, Chang K, Lu LS, et al. Lentivirus-mediated RNA interference targeting the H19 gene inhibits cell proliferation and apoptosis in human choriocarcinoma cell line JAR. BMC Cell Biol 2013;14:26. [Crossref] [PubMed]
  60. Wang SH, Wu XC, Zhang MD, et al. Long noncoding RNA H19 contributes to gallbladder cancer cell proliferation by modulated miR-194-5p targeting AKT2. Tumour Biol 2016. [Epub ahead of print]. [PubMed]
  61. Li W, Jiang P, Sun X, et al. Suppressing H19 Modulates Tumorigenicity and Stemness in U251 and U87MG Glioma Cells. Cell Mol Neurobiol 2016. [Epub ahead of print]. [PubMed]
  62. Bauderlique-Le Roy H, Vennin C, Brocqueville G, et al. Enrichment of Human Stem-Like Prostate Cells with s-SHIP Promoter Activity Uncovers a Role in Stemness for the Long Noncoding RNA H19. Stem Cells Dev 2015;24:1252-62. [Crossref] [PubMed]
  63. Wu T, Qu L, He G, et al. Regulation of laryngeal squamous cell cancer progression by the lncRNA H19/miR-148a-3p/DNMT1 axis. Oncotarget 2016;7:11553-66. [PubMed]
  64. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 2009;69:4116-24. [Crossref] [PubMed]
  65. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418-23. [Crossref] [PubMed]
  66. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52. [Crossref] [PubMed]
  67. Schneider BP, Winer EP, Foulkes WD, et al. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 2008;14:8010-8. [Crossref] [PubMed]
  68. Rakha E, Reis-Filho JS. Basal-like breast carcinoma: from expression profiling to routine practice. Arch Pathol Lab Med 2009;133:860-8. [PubMed]
  69. Desmedt C, Haibe-Kains B, Wirapati P, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res 2008;14:5158-65. [Crossref] [PubMed]
  70. Tang P, Skinner KA, Hicks DG. Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready? Diagn Mol Pathol 2009;18:125-32. [Crossref] [PubMed]
  71. Herschkowitz JI, Simin K, Weigman VJ, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007;8:R76. [Crossref] [PubMed]
  72. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta 2013;1830:2481-95.
  73. Muñoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol 2012;6:620-36. [Crossref] [PubMed]
  74. Ling L, Nurcombe V, Cool SM. Wnt signaling controls the fate of mesenchymal stem cells. Gene 2009;433:1-7. [Crossref] [PubMed]
Cite this article as: Shima H, Yamada A, Ishikawa T, Endo I. Are breast cancer stem cells the key to resolving clinical issues in breast cancer therapy? Gland Surg 2017;6(1):82-88. doi: 10.21037/gs.2016.08.03

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