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Lien, Evan C.

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Lien

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Evan C.

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Lien, Evan C.

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20162

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Author's Publications: search.filters.isAuthorOfPublication.cfdaa276-4d62-4ba9-826e-9bc4976962f7

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    Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis
    (Impact Journals LLC, 2016) Mancini, Maria L.; Lien, Evan C.; Toker, Alex
    One of the most frequently deregulated signaling pathways in breast cancer is the PI 3-K/Akt cascade. Genetic lesions are commonly found in PIK3CA, PTEN, and AKT, which lead to excessive and constitutive activation of Akt and downstream signaling that results in uncontrolled proliferation and increased cellular survival. One such genetic lesion is the somatic AKT1(E17K) mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, we constructed a genetically engineered mouse model that conditionally expresses human AKT1(E17K) in the mammary epithelium. Although AKT1(E17K) is only weakly constitutively active and does not promote proliferation in vitro, it is capable of escaping negative feedback inhibition to exhibit sustained signaling dynamics in vitro. Consistently, both virgin and multiparous AKT1(E17K) mice develop mammary gland hyperplasia that do not progress to carcinoma. This hyperplasia is accompanied by increased estrogen receptor expression, although exposure of the mice to estrogen does not promote tumor development. Moreover, AKT1(E17K) prevents HER2-driven mammary tumor formation, in part through negative feedback inhibition of RTK signaling. Analysis of TCGA breast cancer data revealed that the mRNA expression, total protein levels, and phosphorylation of various RTKs are decreased in human tumors harboring AKT1(E17K).
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    Glutathione biosynthesis is a metabolic vulnerability in PI3K/Akt-driven breast cancer
    (2016) Lien, Evan C.; Lyssiotis, Costas A.; Juvekar, Ashish; Hu, Hai; Asara, John; Cantley, Lewis C.; Toker, Alex
    Cancer cells often select for mutations that enhance signaling through pathways that promote anabolic metabolism1. Although the PI3K/Akt signaling pathway, which is frequently dysregulated in breast cancer2, is a well-established regulator of central glucose metabolism and aerobic glycolysis3,4, its regulation of other metabolic processes required for tumor growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI3K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating Nrf2 to up-regulate the GSH biosynthetic genes. Increased Nrf2 stability is dependent on the Akt-mediated accumulation of p21Cip1/WAF1 and GSK-3 inhibition. Consistently, in human breast tumors, up-regulation of Nrf2 targets is associated with PI3K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI3K/Akt-driven resistance to oxidative stress, initiation of tumor spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine (BSO) synergizes with cisplatin (CDDP) to selectively induce tumor regression in PI3K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI3K pathway mutant breast cancers.