Summary Transforming growth factor-β (TGF-β) plays an essential role in maintaining tissue homeostasis through its ability to induce cell cycle arrest, differentiation, apoptosis, and to preserve genomic stability. Thus, TGF-β is a potent anticancer agent that prohibits the uncontrolled proliferation of epithelial, endothelial, and hematopoietic cells. Interestingly, tumorigenesis typically elicits aberrations in the TGF-β signaling pathway that engenders resistance to the cytostatic activities of TGF-β, thereby enhancing the development and progression of human malignances. Moreover, these genetic and epigenetic events conspire to convert TGF-β from a suppressor of tumor formation to a promoter of their growth, invasion, and metastasis. The dichotomous nature of TGF-β during tumorigenesis is known as the “TGF-β Paradox,” which remains the most critical and mysterious question concerning the physiopathological role of this multifunctional cytokine. Here we review recent findings that directly impact our understanding of the “TGF-β Paradox” and discuss their importance to targeting the oncogenic activities of TGF-β in developing and progressing neoplasms.

Tumorigenesis is in many respects a process of dysregulated cellular evolution that drives malignant cells to acquire six phenotypic hallmarks of cancer, including their ability to proliferate and replicate autonomously, to resist cytostatic and apoptotic signals, and to induce tissue invasion, metastasis, and angiogenesis. Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that functions as a formidable barrier to the development of cancer hallmarks in normal cells and tissues. Paradoxically, tumorigenesis counteracts the tumor suppressing activities of TGF-β, thus enabling TGF-β to stimulate cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant cells overcome the cytostatic actions of TGF-β, and of how TGF-β stimulates the acquisition of cancer hallmarks by developing and progressing human cancers. Here we review the molecular and cellular mechanisms that underlie the ability of TGF-β to mediate tumor suppression in normal cells, and conversely, to facilitate cancer progression and disease dissemination in malignant cells.

Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that regulates mammalian development, differentiation, and homeostasis in essentially all cell types and tissues. TGF-β normally exerts anticancer activities by prohibiting cell proliferation, and by creating cell microenvironments that inhibit cell motility, invasion and metastasis. However, accumulating evidence indicates the process of tumorigenesis, particularly that associated with metastatic progression, confers TGF-β with oncogenic activities, a functional switch known as the “TGF-β Paradox.” The molecular determinants governing the “TGF-β Paradox” are complex and represent an intense area of investigation by researchers in academic and industrial settings. Recent findings link genetic and epigenetic events in mediating the acquisition of oncogenic activity by TGF-β, as does aberrant alterations within tumor microenvironments. These events coalesce to enable TGF-β to direct metastatic progression via the stimulation of epithelial-mesenchymal transition (EMT), which permits carcinoma cells to abandon polarized epithelial phenotypes in favor of apolar mesenchymal-like phenotypes. Attempts to deconstruct the EMT process induced by TGF-β have identified numerous signaling molecules, transcription factors, and microRNAs operant in mediating the initiation and resolution of this complex transdifferentiation event. Besides its ability to enhance carcinoma cell invasion and metastasis, EMT also engenders transitioned cells with stem-like properties, including the acquisition of self-renewal and tumor-initiating capabilities coupled to chemoresistance. Here we review recent findings that delineate the pathophysiological mechanisms whereby EMT stimulated by TGF-β promotes metastatic progression and disease recurrence in human carcinomas.

Transforming growth factor–β (TGF-β) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain–containing mTOR-interacting protein (Deptor), in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α–negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.