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Expression of estrogen receptor in breast cancer stem cells
An important advance in breast cancer treatment was the introduction of adjuvant hormonal therapy, which uses selective anti-estrogens, such as tamoxifen or aromatase inhibitors in the treatment of ER (estrogen receptor) positive tumors. However, for ER+ tumors these hormonal interventions reduce the recurrence rate only by approximately 40-50%. Understanding the molecular mechanisms underlying the hormonal therapy resistance could help in predicting the efficacy of this treatment and eventually in developing alternative therapeutic strategies for the ER- breast cancers and ER+ breast cancers which recur despite anti-estrogen therapy. We and others proposed a model in which a small subset of cancer stem cells are responsible for the cellular heterogeneity of tumors and drive tumorigenesis, carcinogenesis and metastasis. One important implication of the stem cell model of mammary carcinogenesis concerns the relationship between stem/progenitor cells and the population of cells capable of responding to estrogen by virtue of the expression of estrogen receptor. The existence of this cancer stem cell population, with a predictable molecular phenotype (CD44+ CD24-lineage-), was recently demonstrated. We identified ALDH (aldehyde dehydrogenase) as a marker for both normal and cancer stem cells in the breast. The advantage of this unique marker is that it can be used for in situ immunostaining in routine histopathological examination of paraffin embedded sections. We postulate that the transformation of different subsets of stem and progenitor cells results in the diversity of breast cancer phenotypes, including the expression of estrogen receptor in subtypes of breast cancers. Therefore the cancer stem cell population can be derived from either ER+ or ER- stem or progenitor cells, and will generate tumors with different molecular profiles and different clinical outcomes. We propose to test this hypothesis by investigating ER expression in the cancer stem cell population identified by ALDH staining for patients with known clinical outcome. We also propose to use breast cancer cell lines to directly test tumorigenicity of ER+, ER-, ALDH+ and ER- sub-populations of cells upon orthotopic xenotransplantation in NOD/scid mice. The proposed study should help in understanding the basic biology of breast cancer but also in developing more successful preventive and therapeutic strategies for this disease. If our hypothesis is correct, the ER expression in the breast tumorigenic population will correlate with distinct clinical outcomes. This should allow for a more tailored treatment of breast cancer and eventually for therapy targeted against the cancer stem cell population.
Despite advances in early detection and treatment of breast cancer, at the present time metastatic breast cancer remains an incurable disease. An important advance was the introduction of anti-estrogens, such as tamoxifen, in the treatment of estrogen receptor (ER) positive tumors. However, ER- tumors, which are more aggressive and have a very poor outcome, do not benefit from this type of adjuvant therapy. Moreover, 50-60 % of ER+ tumors recur despite hormonal therapy. Understanding the factors that contribute to the occurrence of ER- and ER+ breast tumors and the mechanisms that lead to resistance to anti-estrogen treatment in some ER+ tumors would help tremendously in developing better therapies for breast cancer. Recently a new model for carcinogenesis was proposed. According to this model, only a small subset of cells, termed cancer stem cells, are capable to sustain tumor growth and metastasis. These cancer stem cells are derived through transformation of normal stem cells and early progenitors and retain some of their properties. Cancer stem cells should be the main target of therapy. It is likely that conventional chemotherapy targets the predominant non-tumorigenic cell population, which might account for their failure to cure cancer. On the basis of this stem cell concept, we propose a model in which mutations occurring in different subsets of stem and progenitor cells result in the diversity of breast cancer phenotypes, including the expression of ER in subtypes of breast cancers. ER- tumors arise from mutations affecting the most primitive ER- stem/early progenitor cells and are the most aggressive. A second category arises from the transformation of an ER- stem/early progenitor cells, but allow for the differentiation of a subset of tumor cells into ER+ cells. Although these tumors are ER+, because the ?tumorigenic? component of these tumors is driven by ER- stem cells, the use of anti-estrogens would not have significant preventive effects. A third type of breast tumors may arise from mutated ER+ progenitors. One would predict that these tumors are formed of more differentiated cells, and can be eliminated by anti-estrogen treatment. We propose to test this hypothesis by investigating ER expression in the cancer stem cell population from human breast tumors, using a cancer stem cell marker that we recently identified. Correlation between ER status of the cancer stem cell population and clinical outcome will be investigated. To directly test the hypothesis, ER+ breast cancer cell lines will be sorted based on ER expression and stem cell markers, and the tumorigenicity of the separated sub-populations will be evaluated in animal models. If our hypothesis is correct, the ER expression in the breast tumorigenic population will correlate with distinct clinical outcomes. This should allow for a more tailored treatment of breast cancer and eventually for therapy targeted against the cancer stem cell population.