Abstract
Metabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby sustaining rapid proliferation. Recently, new evidence has emerged that metabolic dysregulation may occur at early-stages of neoplasia and critically contribute to cancer initiation. Here, our bioinformatics analysis of microarray data from early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of canonical glycolytic genes, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human mammary epithelial cells (hMECs) up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation. Knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Mechanistically, 14-3-3ζ overexpression activates the MEK-ERK-CREB axis, which subsequently up-regulates LDHA. In vivo, inhibiting the activated the MEK/ERK pathway in 14-3-3ζ-overexpressing hMEC-derived MCF10DCIS.COM lesions led to effective inhibition of tumor growth. Therefore, targeting the MEK/ERK pathway could be an effective strategy for intervention of 14-3-3ζ-overexpressing early breast lesions. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis and transcriptionally up-regulating LDHA, thereby contributes to human breast cancer initiation.
Highlights
One in five breast cancer patients presents earlystage disease in the clinic, such as atypical ductal hyperplasia (ADH) and/or ductal carcinoma in situ (DCIS) [1]
As increased glycolysis has been implicated in early-stage neoplastic transformation [8], we examined whether 14-3-3ζ-mediated lactate dehydrogenase A (LDHA) upregulation is a critical determinant of human mammary epithelial cells (hMECs) transformation
As the above data demonstrated that the MEK/ ERK/CREB pathway is critical for 14-3-3ζ-induced LDHA upregulation which contributes to hMEC early transformation
Summary
One in five breast cancer patients presents earlystage disease in the clinic, such as atypical ductal hyperplasia (ADH) and/or ductal carcinoma in situ (DCIS) [1]. Given the concomitant 14-3-3ζ overexpression and abnormal metabolic alterations during the early-stage breast disease, we postulated that overexpression of 143-3ζ may lead to increased glycolysis and contribute to early transformation of mammary epithelial cells and subsequent breast cancer initiation/progression. To this end, we examined gene expression profiling data of early-stage neoplastic breast lesions and found a strong correlation between the expressions of 14-3-3ζ and genes of the canonical glycolytic pathway, lactate dehydrogenase A (LDHA). Our data demonstrate that targeting 14-3-3ζ-induced metabolic dysregulation could be an efficacious strategy for prevention and early intervention of early-stage breast cancer
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