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M.S., Shandong University - 2007
Thesis Advisor: Vassiliki Karantza, M.D., Ph.D.
Graduate Program in Cellular & Developmental Biology
Rutgers Cancer Institute of New Jersey
Monday, December 16, 2013
Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase, which is amplified and/or overexpressed in 25-30% of human breast cancer and is associated with poor clinical outcomes. Sequestosome 1 (SQSTM1), also known as p62 in human, is a multifunctional protein involved in a number of signaling pathways and has been implicated in Paget’s disease of bone, neurodegenerative diseases, chronic liver disorders and cancer. Previous tissue microarray studies on human breast tumors showed that HER2 expression significantly correlated with p62 overexpression. Moreover, p62 overabundance has been observed in malignant breast tissues relative to normal breast tissues. However, the role of p62 on the pathophysiology of HER2-induced mammary tumorigenesis has not yet been investigated. We now report that p62 facilitates HER2-mediated cell survival in both two-dimensional and three-dimensional cell culture and that HER2-induced cellular transformation requires p62, as well as Nrf2, which is stabilized by its release from Keap1 via a p62-Keap1 interaction. Furthermore, we found that genetic ablation of p62 delayed HER2-induced mammary tumorigenesis in both athymic mouse allografts and MMTV-Neu transgenic mice. Thus, we investigated the underlying mechanisms by further in vitro and in vivo studies. In vitro, in contrast to their wild type counterparts, p62-/- iMMECs had higher basal levels of phospho-Akt, but failed to further activate it in response to HER2 overexpression. Although more sensitive to amino acid depletion than their wild type counterparts, HER2-expressing p62-deficient iMMECs were more tolerant of glucose and oxygen deprivation. Furthermore, siRNA-mediated p62 knockdown suppressed Akt phosphorylation and â-catenin signaling in the HER2-amplified human breast cancer cell line BT474. In vivo, biallelic p62 deletion reduced ductal side-branching in MMTV-Neu mice, likely as a result of impaired RANKL-NF-êB signaling. Compared to MMTV-Neu mice, mammary glands from p62-/-;MMTV-Neu mice had higher levels of PTEN, which is in agreement with our in vitro results that p62-deficient iMMECs also exhibited higher levels of PTEN, suggesting that p62 may play a role in PTEN stability and turnover.
Summarizing our findings, we propose that p62 regulates HER2-induced mammary transformation and tumorigenesis through multiple signaling pathways, including the PI3K/Akt axis, â-catenin signaling, NF-êB pathway and Nrf2 axis.