O'Brien Ciara S, Howell Sacha J, Farnie Gillian, Clarke Robert B
Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):45-54. doi: 10.1007/s10911-009-9115-y. Epub 2009 Feb 28.
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 ERalpha-. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERalpha and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERalpha+ 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 ERalpha- and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERalpha expression, further indicating the mutual exclusion between ERalpha+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ERalpha 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.
从发育的角度来看，肿瘤可被视为其起源组织的异常形式。例如，肿瘤常常部分保留其起源组织的分化标志物，并且有证据表明它们含有驱动肿瘤发生的癌症干细胞（CSCs）。在本综述中，我们总结了当前的证据，即乳腺CSCs可能部分解释了乳腺癌中的内分泌抵抗。在正常乳腺中，已知干细胞具有基底表型且主要为ERα阴性。如果乳腺癌中的细胞层次反映了这一点，那么乳腺CSC可能具有内分泌抗性，因为它表达很少的ERα，并且只能通过邻近的、分化的ERα阳性肿瘤细胞的旁分泌影响来对治疗作出反应。正常乳腺上皮干细胞高度依赖于表皮生长因子受体（EGFR）和其他生长因子受体，并且可能是在内分泌抵抗性乳腺癌中观察到的生长因子受体表达增加反映了由内分泌疗法选择的CSCs比例增加。多项研究的证据表明乳腺CSCs是ERα阴性且EGFR阳性/人表皮生长因子受体2（HER2）阳性，这将支持这一观点。CSCs还表达被ERα表达抑制的间充质基因，进一步表明ERα阳性细胞与CSCs之间的相互排斥。随着我们对CSCs、分化以及不同乳腺肿瘤亚型中这些细胞中ERα的表达和功能活性了解得更多，希望我们的理解将带来新的方法以克服临床上内分泌抵抗的问题。
