Abstract
Breast cancer screening and new precision therapies have led to improved patient outcomes. Yet, a positive prognosis is less certain when primary tumors metastasize. Metastasis requires a coordinated program of cellular changes that promote increased survival, migration, and energy consumption. These pathways converge on mitochondrial function, where distinct signaling networks of kinases, phosphatases, and metabolic enzymes regulate these processes. The protein kinase A-anchoring protein dAKAP1 compartmentalizes protein kinase A (PKA) and other signaling enzymes at the outer mitochondrial membrane and thereby controls mitochondrial function and dynamics. Modulation of these processes occurs in part through regulation of dynamin-related protein 1 (Drp1). Here, we report an inverse relationship between the expression of dAKAP1 and mesenchymal markers in breast cancer. Molecular, cellular, and in silico analyses of breast cancer cell lines confirmed that dAKAP1 depletion is associated with impaired mitochondrial function and dynamics, as well as with increased glycolytic potential and invasiveness. Furthermore, disruption of dAKAP1-PKA complexes affected cell motility and mitochondrial movement toward the leading edge in invasive breast cancer cells. We therefore propose that depletion of dAKAP1-PKA "signaling islands" from the outer mitochondrial membrane augments progression toward metastatic breast cancer.
Highlights
Breast cancer screening and new precision therapies have led to improved patient outcomes
We show that the loss of dAKAP1 signaling islands from the outer mitochondrial membrane occurs as breast cancer cells acquire a more mesenchymal phenotype
Because dAKAP1 may be involved in the establishment and growth of certain tumors, we sought to establish whether changes in the expression pattern of this anchoring protein could serve as a cellular index of metastatic potential [19, 20]
Summary
The in vivo tumor microenvironment contains two key compartments: tumor cells and the surrounding stroma [20, 26, 27]. In keeping with this notion, only 4% of the primary breast tumors were scored as weakly expressing dAKAP1 as compared with 22% of the metastatic tumors (Fig. 1, G and H, teal) Paired analyses of these 45 matched tissue samples provide further evidence of reduced dAKAP1 tumor staining after metastasis (Fig. 1I). A similar inverse association with dAKAP1 expression was apparent across a variety of cancer etiologies, suggesting that this relationship to mesenchymal markers is broadly conserved across multiple cancer types (Fig. S1, A and B) Correlative analyses in both breast cancer cell lines and tissues further support the notion that dAKAP1 expression is inversely related to a mesenchymallike phenotype (Fig. S1, C–E).
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