Breast tumor heterogeneity: causes and consequences
© BioMed Central Ltd. 2009
Published: 23 June 2009
In breast and other cancer types, a high degree of diversity exists among and within tumors. Breast tumors are composed of a variety of cancer cells with distinct phenotypes and genotypes. The molecular mechanisms responsible for this intratumoral heterogeneity are not well defined. Two currently popular hypotheses that attempt to explain intratumoral heterogeneity are the cancer stem cell and the clonal evolution models. Each of these concepts has been investigated for some time, leading to the accumulation of findings that support one or the other. Although the two views share some similarities, they are fundamentally different notions with very different implications for clinical practice.
To characterize cells with stem-like characteristics, we determined the gene expression, DNA methylation, and genetic profiles of distinct cell populations purified from breast carcinomas and normal breast tissue using cell surface markers CD24 and CD44 that have been associated with stem cell-like properties. Gene expression profiles were analyzed using serial analysis of gene expression, DNA methylation profiles by methylation-specific digital karyotyping, whereas genetic alterations were investigated using SNP arrays and fluorescence in situ hybridization.
SNP array and methylation-specific digital karyotyping analyses suggested that CD24+/CD44- and CD24-/CD44+ cells from the same tumor are clonally related, but can be both genetically and epigenetically distinct. CD44+ cells have an activated TGFβ signaling pathway, whereas it is decreased in CD24+ cells due to TGFβR2 promoter hypermethylation. As a consequence of this, CD44+ cells specifically respond to an inhibitor of TGFβR, and acquire more differentiated epithelial cellular morphology and membrane localization of E-cadherin and β-catenin. Furthermore, gene expression profiling revealed that breast cancer patients with lymph node-negative breast tumors that have a higher fraction of CD44+ cells had shorter overall survival as well as shorter distant metastasis-free survival. In contrast, CD24+cells appeared to be more prevalent in distant metastases even when the primary breast tumor was enriched for CD44+ cells. This suggests that the tumor cells may be altered during the metastatic process, or that CD24+ breast cancer cells are intrinsically more competent for metastasis.
The results of our recent studies investigating breast cancer cells with stem cell characteristics and the genetic diversity of cellular populations within tumors imply multiple layers of heterogeneity and a combination of different molecular mechanisms underlying breast tumor heterogeneity. Understanding these molecular mechanisms will facilitate the development of more effective ways to treat and prevent breast cancer.
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