Engineering Transcription Factors in Breast Cancer Stem Cells

Abstract

Breast cancers are classified in at least six different subtypes (normal-like, luminal A, luminal B, Her2, basal-like, claudin-low), which are characterized by distinct genome-wide transcriptional profiles and response to therapy [1]. Recently, it has been shown that these intrinsic types of breast cancers are associated with unique DNA-methylation patterns [2,3,4]. In 2009, a large-scale genomic analysis of breast cancer cohorts has identified a novel subtype of breast cancer enriched in putative cancer stem-cell (CSC) markers, named claudin-low [5]. In addition to cancer or stem cell signatures, claudin-low tumors are enriched in Epithelial-to-Mesenchymal transition (EMT) markers, such as high expression of the Transcription Factors (TFs) Twist and Snail, and loss of epithelial junction proteins, such as cadherins, claudins and ocludins. Together with basal-like breast cancers, claudin-low carcinomas are mostly triple negative, hence their lack of expression of the Estrogen Receptor (ER), Progesterone Receptor (PR) and Her2. Consequently, these carcinomas are refractory to regimens to treat breast cancers, such as anti-estrogens and conventional chemotherapy. Similarly to these breast cancers, a subtype of serious epithelial ovarian cancers also appear to be poorly differentiated, high grade, and associated with poor clinical outcome. These serous epithelial ovarian tumors, named type II, are often associated with p53 and BRCA mutations [6]. Thus, there is a need to develop novel and more effective strategies to target poorly differentiated carcinomas. This will begin with a better understanding of molecular pathways that are activated in these tumors, which maintain aberrant proliferation and potentially, tumor initiation. Little is known regarding the molecular determinants of tumor initiation and progression in poorly differentiated cancers. it has been proposed that claudin-low and basal-like breast tumors are originated by oncogenic transformation of bipotent stem and progenitor cells, respectively. Consistent with this idea, we found that many Transcription Factors (TFs) normally expressed in both, adult and embryonic stem cells (hESCs), are also over-expressed in poorly differentiated breast and ovarian carcinomas. In the first part of this chapter we will overview oncogenic TFs and TF networks that could play a role in maintaining aberrant selfrenewal, with special focus on the OCT4-SOX2-NANOG embryonic TF network. In addition to abnormal reactivation of oncogenic TFs, tumor suppressor genes undergo epigenetic silencing