Abstract
Leukemia inhibitory factor (LIF) is a multi-functional cytokine protein. The role of LIF in tumorigenesis is not well-understood. Here, we found that LIF promotes tumorigenesis and metastasis of breast cancer. LIF promotes cell proliferation and anchorage-independent growth of breast cancer cells in vitro, and the growth of xenograft breast tumors in vivo. LIF also promotes invasion and migration of breast cancer cells in vitro and metastasis of breast cancer in vivo. We found that LIF activates the AKT-mTOR signaling pathway to promote tumorigenesis and metastasis of breast cancer. Inhibiting the AKT activity can largely block the activation of the mTOR pathway by LIF, suggesting that LIF activates the mTOR pathway through AKT. Inhibiting the AKT activity as well as inhibiting the mTOR activity largely block the promoting effect of LIF on tumorigenesis and metastasis. Furthermore, overexpression of LIF is significantly associated with a poorer relapse free survival in breast cancer patients. Taken together, our data strongly suggest that LIF plays an important role in the tumorigenesis and metastasis of breast cancer, and could be an important prognostic marker for breast cancer.
Highlights
Breast cancer is one of the most common malignant tumors and the second most common cause of cancer related deaths in the United States
The mTOR pathway is frequently activated in various cancers, including breast cancer, which plays a critical role in tumor growth and metastasis [34,35,36]
Blocking AKT activity by wortmannin or the expression of dominant negative AKT (DN-AKT) largely abolished the activation of mTOR by Leukemia inhibitory factor (LIF), and more importantly, largely abolished the promoting effect of LIF on tumorigenesis and metastasis of breast cancer
Summary
Breast cancer is one of the most common malignant tumors and the second most common cause of cancer related deaths in the United States. Limited studies suggested the potential complex role of LIF in cancer www.impactjournals.com/oncotarget depending upon the types of the cancer. LIF could inhibit the differentiation and promote proliferation in some cancers and cancer cell lines, and has been suggested to contribute to the progression of malignancies, including rhabdomyosarcoma, choriocarcinoma and melanoma [8, 16,17,18]. LIF has been reported to induce the differentiation of murine myeloid leukemia cells and inhibit proliferation and growth in some other cancer cell lines [19,20,21]. The detailed function of LIF in breast cancer remains unclear
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