Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells

McMurtry, Vanity; Simeone, Ann-Marie; Nieves-Alicea, René; Tari, Ana M.

doi:10.1007/s10585-008-9231-x

Cited by 34 publications

(36 citation statements)

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“…Castellucci et al (2000) reported that leptin dose-dependently enhances secretion of MMP-2 and the activity of MMP-9 in cultured cytotrophoblastic cells. Consistent with this finding, McMurtry et al (2009) demonstrated that activated Janus-activated kinase 2 (JNK) led to enhanced MMP-2 activity, and ultimately caused an increase of MCF-7 human breast cancer cell invasion.…”

Section: Leptin and Tumor Invasionsupporting

confidence: 53%

Roles of Leptin in Cancer Progression

Kang¹,

Moon

2010

Biomolecules and Therapeutics

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-Growing evidence suggests a prominent role for leptin in human cancer progression. The intricate pattern of leptin cross-talk with other associated signaling pathways is a critical area of research that will ultimately contribute to comprehending the role of leptin in cancer progression. This review summarizes a portion of the current understanding of leptin signaling, with a critical focus on its contribution to tumor cell invasion and metastasis. Five topics are addressed in this review: (1) Leptin receptor, (2) Leptin signaling, (3) Leptin and cancer, and (4) Leptin and tumor invasion. Due to the complex cellular effects of leptin, a more precise understanding of leptin signaling pathways must still be elucidated. Leptin is clearly a major factor for stimulating tumor progression through a complex spectrum of interplay and cross-talk among various signaling molecules. An understanding of the role of leptin in invasion and metastasis will provide valuable information for establishing strategies to modulate leptin signaling, which should be a high priority for the development of anti-cancer therapeutics.

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Section: Leptin and Tumor Invasionsupporting

confidence: 53%

Roles of Leptin in Cancer Progression

Kang¹,

Moon

2010

Biomolecules and Therapeutics

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“…The invasiveness of MCF-7 and MCF-7/ PDCD4 cells treated with leptin was determined as previously described (14,19) by counting the number of cells that invaded through transwell inserts coated with the Matrigel artificial basement membrane. Briefly, MCF-7 and MCF-7/PDCD4 cells were collected and washed with serum-free media.…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was performed as described (14). Cells were harvested with cold PBS, and lysed with ice-cold lysis buffer and incubated on ice for 30 min.…”

Section: Rna Isolation and Reverse Transcription-polymerase Chain Reamentioning

confidence: 99%

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Programmed cell death 4 inhibits leptin-induced breast cancer cell invasion

et al. 2011

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Abstract. Obesity is a significant risk factor for post-menopausal women to develop and die from breast cancer. Leptin, an adipokine is produced in high levels in obese individuals, and its receptor is overexpressed in breast tumors and lymph node metastases. Previously, we demonstrated that leptin stimulates breast cancer cell invasion, which is correlated with breast cancer metastasis. Programmed cell death 4 (PDCD4) has been shown to block cancer cell invasion. However, whether PDCD4 blocks leptin-induced breast cancer cell invasion is not known. Here, we report the novel findings that leptin failed to induce invasion in MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4). Tissue inhibitor of metalloproteinase-2 (TIMP-2) was essential to the anti-invasive effect of PDCD4, as leptin stimulated the invasion of MCF-7/ PDCD4 cells pretreated with TIMP-2 siRNA. Furthermore, TIMP-2 knockdown allowed leptin to augment phosphorylation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3, but not that of Jun N-terminal kinases. These data indicate that PDCD4 utilizes TIMP-2 to exert its anti-invasive effect by suppressing leptininduced activation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity-related breast tumor progression and prolong the life of patients. IntroductionBreast cancer is the most frequently diagnosed cancer in women. In 2010, about 207,090 new cases of invasive breast cancer were expected to be diagnosed among women, and about 39,840 women were expected to die from breast cancer. One of the major risk factors for postmenopausal women to develop breast cancer is obesity. Tumors from breast cancer patients with high body mass index are typically of the hormoneresponsive type (1-3). Leptin, a 16-kDa hormone that was discovered as a regulator of body weight and energy balance acting in the hypothalamus (4), is an important hormonal link between obesity and breast cancer. As body weight and fat mass increase, the level of circulating leptin increases (5,6).High expression of leptin and the long/signaling form of leptin receptor have been found in breast tumors (7-11). Leptin-deficient mice have decreased incidence of oncogeneinduced mammary tumors (12). An inhibitor targeted to the leptin receptor suppresses breast tumor formation in vivo (13). High levels of leptin in breast tumors have been correlated with poorer patient prognosis and increased incidence of metastasis (7,10,11). Breast cancer metastasis is directly associated with breast cancer cell invasion. Recently, we showed that leptin stimulates invasion of MCF-7 breast cancer cells by activating Jun N-terminal kinases (JNK), which increase matrix metalloproteinase-2 activity (14).Leptin has also been associated with the development of anti-estrogen resistance. Leptin is a potent modulator of the estrogen receptor signaling pathwa...

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“…In vitro studies demonstrate that leptin stimulates breast cancer cell growth and survival. The hormone can also increase the invasiveness and metastatic potential of BC cells [15], and promote angiogenesis while maintaining a microenvironment favorable for BC development [16]. Furthermore, leptin is known to crosstalk with and transactivate several pathways that are targets for BC therapy, including the estrogen, EGF receptor and HER2 pathways [13,17,18].…”

Section: Themed Article Y Breast Cancermentioning

confidence: 99%