Breast Cancer Progression: Controversies and Consensus in the Molecular Mechanisms of Metastasis and EMT

Abstract

Breast cancer is the second most frequent form of female cancer and a major source of cancer death worldwide. Although breast cancer has long been part of the human condition, appearing in the writings of ancient Egyptians, modern breast cancer shows a disturbing statistical increase from 1 per 20 women in the 1960s to one in eight today [1]. Although early detection by mammography and adjuvant therapies has improved survival, the absence of good prognostic criteria continues to result in overtreatment of patients with benign disease and failure to identify and eliminate the source of metastatic breast cancer.This issue is concerned with the myriad stages of tumor progression that lead to the dissemination of breast cancer cells from the primary tumor and propagation at distant sites. The first stage in this progression involves loss of local constraints, both physical and regulatory, emanating from neighboring normal cells and surrounding stroma. The second step termed intravasation, involves entering a circulatory system (blood and/or lymphatic), the third dissemination and survival within hostile ectopic environments, and the fourth organotropic colonization of compatible sites.Considerable debate has arisen between elements in the scientific and clinical community concerning the proposed mechanisms of metastatic spread [2,3]. The controversy centers on whether metastasis involves inappropriate transient re-enactment of developmental migratory processes; Darwinian selection within a population of genomically unstable, rapidly evolving cancer cells for attributes that facilitate growth in and exploitation of new environs; or a combination of both.Seeing parallels between the metastatic process and the long-distance migration of cells during development, cell and developmental biologists have invoked epithelial-mesenchymal transition (EMT) as the mechanistic basis for breast cancer metastasis [4][5][6]. In its strictest sense, EMT and its converse MET, have been used to describe conversions in cell shape and migratory behavior that accompany cell fate changes during embryonic development. A classical example of EMT is the emergence from the coherent neural plate of migratory neural crest cells, which travel long distances and adopt many different mesenchymal cell fates. These events involve the loss of "epithelial" characteristics such as cell-cell adhesion mechanisms and junctions and switching on of vimentin expression as the major intermediate filament protein. Further analyses have revealed the essential role of a genetic program tightly

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

“…6 In cancer research, the term EMT has been more inclusively referred to as a change of cytological phenotype characterized as loss of cell junction and gain of migratory behaviors. 40,45 In the present study, we demonstrated that deposition of TNC is frequently observed in invasion fronts of cancer cells with a scattered morphology, and that TNC induces EMT-like morphological change of MCF-7 cells, featuring loss of intercellular connections and an increasingly locomotive phenotype. The similar morphological change of MCF-7 cells on TNC substratum previously has been reported, but it was not mentioned as EMT.…”

“…38 However, whether classic EMT, including an ordered series of transcriptional events and a switch in cell fate observed in embryogenesis, occurs during tumor invasion and metas- tasis is still controversial. 39,40 In ductal carcinomas of the breast, immunohistochemical studies have not demonstrated any apparent correlation of E-cadherin expression with the scattered morphology, tumor type, nodal status, disease recurrence, distant metastases, or other prognostic factors. [41][42][43][44] These observations suggest that a complete transition to a mesenchymal phenotype associated with transcriptional switching is not required for increased malignancy.…”

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

“…Previous studies have suggested that metastatic progression may involve transient EMT that facilitates the migratory behavior of cancer cells (Cowin and Welch, 2007). In this regard, it is interesting to note that elevated expression of ILK in either established mammary epithelial cell or primary mammary epithelial cells is associated with an EMT phenotype (Somasiri et al, 2001;White et al, 2001).…”

Histone Deacetylase Inhibitor Entinostat Inhibits Tumor-Initiating Cells in Triple-Negative Breast Cancer Cells

“…EMT is often activated in tumors during invasion and metastasis and helps cancer cells detach from solid tumors. EMT is characterized by loss of intracellular adhesion (loss of E-cadherin); loss of epithelial markers such as cytokeratins 8/18 and upregulation of mesenchymal markers such as vimentin and acquisition of fibroblastlike spindle morphology and increased motility (3,4). Previously, we showed that treatment of triple-negative cells of basal origin that have a mesenchymal phenotype with HDAC inhibitor entinostat results in reversal of EMT phenotype and reduction in migratory capacity (5).…”