Cellular Processes

It has been shown that MCF-7 cells present very low levels of metastasis (31, 32)

It has been shown that MCF-7 cells present very low levels of metastasis (31, 32). was significantly correlated with Snai1 positivity. Notably, in these patients elevated expression of Pit-1 was significantly and independently associated with the occurrence of distant metastasis. These findings suggest that Pit-1 could help to make a more accurate prognosis in patients with node-positive breast cancer and may represent a new therapeutic target. Introduction Significant clinical effects from cancer result from the development of metastatic disease. The metastasis of breast malignancy is often a multistep event, comprising invasion of mammary carcinoma cells into the adjacent tissues, access of tumor cells in the systemic blood circulation, SU14813 double bond Z extravasation to distant organs, and finally metastatic colonization, mainly to bones, lungs, and central nervous system (1). To develop metastasis, epithelial mammary cells need to break their intercellular adhesion complexes (i.e., adherent, tight, and space junctions and desmosomes), as well as their basement membrane that separates the epithelium from other tissues, and acquire motility to invade adjacent tissues. One of the main processes involved in the change from immobile epithelial cells to mobile mesenchymal cells is the epithelial-mesenchymal transition (EMT). EMT is usually a crucial process that occurs during physiological embryonic development, when epithelial cells acquire a motile morphology appropriate for migration and formation of numerous organs and tissues (2). Mesenchymal cells may again acquire a fully differentiated epithelial phenotype via a mesenchymal-to-epithelial transition (MET). In addition to the physiological role of EMT/MET, it is now known that EMT is usually a mechanism for carcinoma progression, inducing mammary neoplastic epithelial cells to acquire mesenchymal malignant characteristics, such as motility, invasiveness, and resistance to apoptosis, thereby contributing to the formation of metastasis (3). Acting as physiological regulators of EMT during the embryonic development, several transcription factors, including Twist, Snai1, Slug, Goosecoid, FOXC2, or SIX-1, have also been shown to be also involved in the metastatic process (4C8). In addition, a recent study by Mani et al. (9) exhibited that this induction of SU14813 double bond Z EMT either by Twist or Snai1 in human mammary epithelial cells results in the acquisition of both mesenchymal and stem cell characteristics. These authors also Splenopentin Acetate found that stem-like cells isolated from human mammary glands experienced markedly increased expression of EMT markers, including Twist and Snai1, suggesting a strong relation between the EMT process and stem-like cells. POU class 1 homeobox 1 (Pit-1, also known as POU1F1/GHF-1) belongs to the Pit-Oct-Unc (POU) family of transcription factors that play a key role in inhibition and promotion of cell proliferation and determination of cell lineages as well as in regulation of cell migration, survival, and terminal differentiation (10). Pit-1 is critical for cell differentiation during organogenesis of the anterior pituitary gland in mammals (11) and as a transcriptional activator for pituitary gene transcription (i.e., transcription of prolactin [PRL], growth hormone [GH], and Pit-1 itself) (12C14). Mice with inactivating mutations or deletions of the gene fail to generate somatotropes, lactotropes, and thyrotropes and consequently exhibit anterior pituitary hypoplasia SU14813 double bond Z and dwarfism (15), demonstrating the importance of Pit-1 in the ontogeny of the pituitary gland. However, Pit-1 is also expressed in nonpituitary cell lines and tissues, such as human placenta, hemapoietic lymphoid tissues, and human breast (16C20). In these extrapituitary tissues it has been suggested that Pit-1 could also be related to cell proliferation and tumorigenesis (21, 22). Specifically in breast, Pit-1 presents higher expression in tumors than in normal breast, increases cell proliferation, and regulates the expression of 2 breast cancer-related hormones, GH and PRL (20, 23, 24). To analyze the function of Pit-1 in mammary carcinogenesis, the present study uses human mammary cell lines and immunodeficient mice to evaluate the effects of overexpression and knockdown of Pit-1 on important features of the carcinogenic and metastatic process. Moreover, we.