The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells

Abstract

Epithelial-mesenchymal transition (EMT) is an essential process that drives polarized, immotile mammary epithelial cells (MECs) to acquire apolar, highly migratory fibroblastoid-like features. EMT is an indispensable process that is associated with normal tissue development and organogenesis, as well as with tissue remodeling and wound healing. In stark contrast, inappropriate reactivation of EMT readily contributes to the development of a variety of human pathologies, particularly those associated with tissue fibrosis and cancer cell invasion and metastasis, including that by breast cancer cells. Although metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby EMT mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis, and EMT. In addition, TGF-β also functions as a powerful tumor suppressor in MECs, whose neoplastic development ultimately converts TGF-β into an oncogenic cytokine in aggressive late-stage mammary tumors. Recent findings have implicated the process of EMT in mediating the functional conversion of TGF-β during breast cancer progression, suggesting that the chemotherapeutic targeting of EMT induced by TGF-β may offer new inroads in ameliorating metastatic disease in breast cancer patients. Here we review the molecular, cellular, and microenvironmental factors that contribute to the pathophysiological activities of TGF-β during its regulation of EMT in normal and malignant MECs.

Critical role of miR-10b in transforming growth factor-β1-induced epithelial–mesenchymal transition in breast cancer

“…4,[29][30] However, pathological EMT is increasingly recognized to have an important role during the development of human diseases, including chronic inflammation, fibrosis, rheumatoid arthritis and cancer invasion and metastasis. 3,[31][32] miRNAs are endogenous small non-coding RNAs that control the target gene expression at the post-transcriptional level. Several miRNAs have been functionally classified as proto-oncogenes or tumor suppressors and are aberrantly expressed in different cancer types.…”

Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses

“…Activation or aberrant overexpression of transcription factors such as HOXB9 in tumors may induce tumoral expression of growth factors, resulting in their local increase in the tumor microenvironment (1). TGF-β, a pleiotropic cytokine and a potent inducer of EMT, promotes tumor progression through autocrine and paracrine mechanisms (3,12). Ionizing radiation has been shown to induce EMT and invasion of cells through chronic activation of the TGF-β pathway (13,14), suggesting that TGF-β may influence radiation responses by modulating tumor cell fate.…”

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…Since TGF- β has a bimodal role in breast cancer progression, serving as a tumor suppressor at early stages and an oncogene at later stages, the role of MSC-derived TGF- β is complex [15, 33, 34]. The secretion of TGF- β from MSCs would be expected to protect against metastasis based on the inhibitory role of TGF- β on epithelial cell cycle progression [33].…”