[Rich66]

Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits?
(10 pg. PDF attached below)
Ciara S. O’Brien & Sacha J. Howell & Gillian Farnie &
Robert B. Clarke
Received: 16 December 2008 / Accepted: 10 February 2009 / Published online: 28 February 2009
# Springer Science + Business Media, LLC 2009

"The concept that epithelial and other solid tumors are aberrantly developed tissues containing a developmental hierarchy including cancer stem-like cells (CSCs) and more differentiated progenitor cells is supported by accumulating evidence."

"There is no doubt that the evidence that CSCs are responsible for tumorigenesis and cancer recurrence is becoming increasingly solid and needs to be considered for therapeutic decision-making in the clinic."

"A common theme of many investigations into CSCs is that they have inherent resistance to chemo and radiotherapy. This is proposed to be due to mechanisms such as more efficient DNA damage checkpoints and survival pathways compared to more differentiated tumor
cell populations."

"Enhanced interaction between estrogen receptor signalling and growth factor tyrosine kinase pathways such as EGFR, HER2/erbB2 and IGFR mediates resistance to endocrine therapy"


"HDAC inhibitors are being used in a number of on going clinical trials including a phase II trial evaluating vorinostat in ER positive patients with metastatic breast cancer who failed prior aromatase inhibitor therapy and up to three chemotherapy regimes [95]. A report of preliminary findings presented at ASCO 2008 showed that out of the 17 enrolled patients 21% had a partial response and 29% had stable disease after treatment with vorinostat 400 mg daily for 3 of 4 weeks and tamoxifen 20 mg daily,
continuously. These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity."



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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Concluding Remarks
In this review, we have summarised current evidence that supporting improving our understanding of CSCs in order to explain endocrine resistance in breast cancer. The biology of breast CSCs is becoming better characterized and the data suggest that they may be resistant to several
forms of cancer therapy through diverse mechanisms. In terms of responsiveness to endocrine therapy, we can learn about CSC biology and hierarchies in breast cancer by examining what is known about the developmental hierarchy of the normal breast epithelium (Fig. 1). In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ER−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ER and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ER+ 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 resistant breast cancers reflects an increased proportion of stem-like
cells selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ER− which would support this view. CSCs also express mesenchymal proteins which are suppressed by ER expression, further indicating the mutual exclusion between ER+ cells and the CSCs. It is likely that this is regulated at the epigenetic level, and differences in DNA methylation and chromatin organization can be observed between breast CSCs and more differentiated populations. This may in turn be regulated extrinsically by the influence of stromal elements including the stem cell
niche microenvironment associated with the vasculature, the lymph nodes and the bone marrow to which breast cancer cells often metastasise. It is known that the epigenetic programming can be remodeled by using drugs, particularly those that change the methylation and chromatin patterns of
the DNA. Such drugs can effectively differentiate the cells, including potentially the CSCs, leading to a reduction in growth factor receptors and an increase in ER+ cells, which may overcome resistance to endocrine agents in combination therapy. Such combinations are currently in clinical
trials and their outcome is eagerly anticipated. As we learn more about CSCs, differentiation and the expression and functional activity of the ER in these cells in diverse tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine
resistance in the clinic.