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Guiding Breast Cancer Therapy through Epigenetic Analysis

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Review of “A distinct DNA methylation signature defines breast cancer stem cells and predicts cancer outcome” from Stem Cells by Stuart P. Atkinson

Stem cells and their tumorigenic alter egos cancer stem cells (CSCs) share many key properties, although CSCs are also posited to promote tumour growth, evolution, and drug resistance [1]. Understanding what regulates CSCs in specific tissues, such as for breast cancer, will inform on drug regimens and may allow us to predict cancer outcomes. Researchers at the laboratory of Christophe Ginestier (CRCM, Inserm, Marseille, France) have now begun to study the DNA methylation landscape of breast CSCs (bCSCs), after noting that DNA demethylating agent treatment is able to efficiently eliminate various CSCs [2]. Now, in an article in Stem Cells, they report their findings; their determination of the DNA methylation patterns of bCSCs has uncovered important genetic components controlling bCSCs, which impact on the aggressivity and therefore the prognosis for the patient [3].

The group isolated ALDEFLUOR‐positive (bCSCs) [1] and ALDEFLUOR‐negative (non‐bCSCs) populations from five breast cancer lines and established their DNA methylation landscape using whole genome promoter arrays. This allows for the identification, evaluation, and isolation of stem and progenitor cells based on aldehyde dehydrogenase (ALDH), expression and not their cell surface phenotype. Initial analysis found a significant enrichment of PRC1/2 targets in hypermethylated promoters in bCSCs, similar to that observed in embryonic stem cells (ESCs) [2]. Significance analysis of microarrays (SAM) analysis led to the identification of 68 differentially methylated regions (DMRs) representing a bCSCs DMR signature. These regions were hypomethylated in bCSCs and only one region corresponded to a CpG island. Differentiation of bCSCs led to an increase in DNA methylation suggesting that the hypomethylated state is characteristic of immature cancer cells , similar to that that observed for normal blood and skin stem cells [3]. The group went on to identify three key signalling networks that were represented by the bCSC DMR-associated genes; NFKB RB1 and TGFB1, and then analysed these networks in various breast tumours. This demonstrated that only TGFB1‐related genes correlated with the DNA methylation differences, leading to an over expression of such genes. Interestingly, TGFβ treatment increased both ALDEFLUOR‐positive cell number and tumorsphere formation in a breast cancer cell line, whilst blocking of several TGFB1‐related genes reduced bCSC number. Finally, the authors assessed a correlation between the bCSCs DMRs signature and clinical outcome. Interestingly, tumors with a bCSC-DMR signature were more likely to be associated with the TNBC (Triple Negative Breast Cancer) phenotype or the claudin-low breast cancers, which express many stem cell features and tend to be more aggressive [4]. Furthermore the bCSC-DMR signature was associated with a decrease in relapse‐free survival (RFS) (See Figure).

Previous studies have linked gene expression profiles in bCSCs with a clinical outcome [1, 2], and in this study the authors have extended this out to demonstrate that a DNA methylation profile may promote these changes, and furthermore, that this profile can be effectively used to predict prognosis, and potentially aid the therapeutic decision making. The group also highlighted TGFβ as an important regulatory hub for bCSCs and therefore may represent an effective target to reduce bCSC number and therefore prevent evolution and spread of the tumour.

Discussion

  • Is there a similar scenario in different tissues?
  • Are there common epigenetic changes which occur in different tissues?
  • Can we utilise this to create an effective therapeutic?
  • Is epigenetic testing cost-effective and suitable for clinical translation?

References

  1. Visvader JE and Lindeman GJ Cancer stem cells: current status and evolving complexities. Cell Stem Cell 2012;10:717-728.
  2. Tsai HC, Li H, Van Neste L, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 2012;21:430-446.
  3. ElHelou R, Wicinski J, Guille A, et al. A distinct DNA methylation signature defines breast cancer stem cells and predicts cancer outcome. Stem Cells 2014;
  4. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer research 2009;69:1302-1313.
  5. Feinberg AP, Ohlsson R, and Henikoff S The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006;7:21-33.
  6. Bock C, Beerman I, Lien WH, et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Molecular cell 2012;47:633-647.
  7. 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 research 2009;69:4116-4124.
  8. Liu R, Wang X, Chen GY, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. The New England journal of medicine 2007;356:217-226.
  9. Charafe-Jauffret E, Ginestier C, Bertucci F, et al. ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program. Cancer research 2013;73:7290-7300.