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Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits?

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Abstract

From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis. In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ERα−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERα and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERα+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ERα− and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERα expression, further indicating the mutual exclusion between ERα+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ERα in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.

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Abbreviations

CSC:

Cancer stem-like cells

ER:

Estrogen receptorα

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial mesenchymal transition

LN:

Lymph node

ALDH1:

Aldehyde dehydrogenase 1

HDAC:

Histone deacetylase

DNMT:

DNA methyl transferase

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Acknowledgements

Ciara S. O’Brien is a Cancer Research UK Clinical Training Fellow and Sacha Howell is funded by the Christie Hospital NHS Trust Endowments. Gillian Farnie and Robert Clarke are funded by Breast Cancer Campaign grants 2008MaySF01 and 2006MaySF01, respectively.

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  1. Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK

    Ciara S. O’Brien, Sacha J. Howell, Gillian Farnie & Robert B. Clarke

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  1. Ciara S. O’Brien
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  2. Sacha J. Howell
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  3. Gillian Farnie
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  4. Robert B. Clarke
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Correspondence to Robert B. Clarke.

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O’Brien, C.S., Howell, S.J., Farnie, G. et al. Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits?. J Mammary Gland Biol Neoplasia 14, 45–54 (2009). https://doi.org/10.1007/s10911-009-9115-y

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