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.