Negative regulation of UCP2 by TGFβ signaling characterizes low and intermediate-grade primary breast cancer

Abstract

The histological manifestation of growth-regulating and differentiation-inducing signals in cancer cells is considered as a key component for clinical outcome prediction and commonly defined as tumor differentiation grade. However, the molecular and functional framework underlying this clinical parameter remains poorly understood. Our correlative data display a significant association (P>0.001) between mitochondrial uncoupling protein 2 (UCP2) and tumor grade in primary breast cancer (n=234). Through mechanistic analyses, we show a synergistic link between UCP2 and established cellular pathways in conferring grade-associated functional phenotypes. Here, the application of well to moderately differentiated primary tumor cell lines has enabled direct observation of SMAD recruitment to the UCP2 promoter underlying repression of gene transcription. In contrast, poorly differentiated tumor cells, known to be TGFβ resistant, displayed aberrant UCP2 regulation, and consequently, gene overexpression, which reduced mitochondrial calcium and facilitated the maintenance of mitochondrial membrane potential, thereby significantly decreasing oxidative stress and inhibiting cell death. Conversely, UCP2 silencing in such cells rapidly led to the induction of apoptosis and cell differentiation, concurrent with reduced cell survival and proliferation, confirming gene-specific effects. Demonstration of a biologically driven role for UCP2 dysregulation in promoting multiple characteristics of tumor aggressiveness strongly endorses assessment of gene expression at clinical presentation to augment therapeutic decision-making and improve patient outcome through personalized targeting approaches.

Multiple blocks in the engagement of oxidative phosphorylation in putative ovarian cancer stem cells: implication for maintenance therapy with glycolysis inhibitors

“…It is important to note that the demonstration that EOC stem cells have higher levels of UCP2 yet also have higher MMP is not contradictory to what is currently known about UCP2. Previous studies have demonstrated UCP2 knock-down may further increase MMP [44] hence suggesting that UCP2 activity may be depend on cell type or cellular status.…”

Transforming Growth Factor-β, Bioenergetics, and Mitochondria in Renal Disease

“…In breast tumor cells TGF-β/Smad signaling regulates mitochondrial uncoupler UCP2 expression to maintain a well differentiated and low proliferating phenotype associated with a good clinical prognosis 39 . In TGF-β-resistant grade 3 tumor cells, elevated expression of UCP2 is associated with increased tumor cell survival and proliferation 39 . In preglomerular afferent arteriolar smooth muscle cells TGF-β depresses angiotensin II or endothelin-evoked calcium signaling.…”

UCP2 Knockout Suppresses Mouse Skin Carcinogenesis

“…Upregulation of UCP2 has been reported in human colon (5) and breast (7) cancers. Our recent studies also reveal that UCP2 is overexpressed in human skin, head & neck, pancreatic and prostate tumor tissues compared with the adjacent normal tissues (6). It has been proposed that upregulation of UCP2 may serve as a novel survival mechanism for cancer cells, which is thought to be mediated by lowering ROS generation (24).…”