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1.  ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis 
Oncogene  2012;33(2):212-224.
Reduced expression of the p53 family member p63 has been suggested to play a causative role in cancer metastasis. Here we show that ΔNp63α, the predominant p63 isoform, plays a major role in regulation of cell migration, invasion, and cancer metastasis. We identified MAP Kinase Phosphatase 3 (MKP3) as a downstream target of ΔNp63α that is required for mediating these effects. We show that ΔNp63α regulates Extracellular Signal-Regulated Protein Kinase 1 and 2 (Erk1/2) activity via MKP3 in both cancer and non-transformed cells. We further show that exogenous ΔNp63α inhibits cell invasion and is dependent on MKP3 up-regulation for repression. Conversely, endogenous pan-p63 ablation results in increased cell migration and invasion, which can be reverted by reintroducing the ΔNp63α isoform alone, but not by other isoforms. Interestingly, these effects require Erk2, but not Erk1 expression, and can be rescued by enforced MKP3 expression. Moreover, MKP3 expression is reduced in invasive cancers, and reduced p63 expression increases metastatic frequency in vivo. Taken together, these results suggest an important role for ΔNp63α in preventing cancer metastasis by inhibition of Erk2 signaling via MKP3.
PMCID: PMC3962654  PMID: 23246965
p63; MKP3; Erk; metastasis; cancer
3.  Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis 
Oncogene  2011;30(25):2836-2845.
The major heat shock protein Hsp72 is expressed at elevated levels in many human cancers and its expression correlates with tumor progression. Here we investigated the role of Hsp72 in Her2 oncogene-induced neoplastic transformation and tumorigenesis. Expression of Her2 in untransformed MCF10A mammary epithelial cells caused transformation, as judged by foci formation in culture and tumorigenesis in xenografts. However, expression of Her2 in Hsp72-depleted cells failed to induce transformation. The anti-tumorigenic effects of Hsp72 downregulation were associated with cellular senescence due to accumulation of p21 and depletion of survivin. Accordingly, either knockdown of p21 or expression of survivin reversed this senescence process. Further, we developed an animal model of Hsp72-dependent breast cancer associated with expression of Her2. Knockout of Hsp72 almost completely suppressed tumorigenesis in the MMTVneu breast cancer mouse model. In young Hsp72 KO mice, expression of Her2 instead of mammary tissue hyperplasia led to suppression of duct development and blocked alveolar budding. These effects were due to massive cell senescence in mammary tissue, which was associated with upregulation of p21 and downregulation of survivin. Therefore Hsp72 plays an essential role in Her2-induced tumorigenesis by regulating oncogene-induced senescence pathways.
PMCID: PMC3433756  PMID: 21297664
Hsp72; HER2; senescence; p21; survivin
4.  Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells 
Aging cell  2011;10(6):949-961.
Activation of the Her2 (ErbB2) oncogene is implicated in the development of breast, ovary and other cancers. Here, we show that expression of NeuT, a mutant-activated rodent isoform of Her2, in immortalized breast epithelial cells, while promoting senescence associated morphological changes, up-regulation of senescence associated β-galactosidase activity, and accumulation of the cyclin-dependent kinase inhibitor p21, failed to trigger the major senescence end-point, i.e. permanent growth arrest. Similar senescence-associated phenotype with incomplete growth arrest, which we dubbed senescence with incomplezXte growth arrest (SWING), could also be triggered by the expression of the Ras oncogene. SWING phenotype was stable, and persisted in tumor xenografts established from NeuT-transduced cells. Furthermore, a significant population of cells in SWING state was found in tumors in the MMTV/NeuT transgenic mouse model. SWING cells showed downregulation of histone H2AX, critical for repair of double-stranded DNA breaks, and impaired activation of Chk1 kinase. Overall, SWING cells were characterized by increased DNA instability and hypersensitivity to genotoxic stresses. We propose that the SWING state could be a stage in the process of cancer development.
PMCID: PMC3433764  PMID: 21824272
DNA damage response; Her2; oncogenes; senescence
5.  Heat Shock Transcription Factor Hsf1 Is Involved in Tumor Progression via Regulation of Hypoxia-Inducible Factor 1 and RNA-Binding Protein HuR 
Molecular and Cellular Biology  2012;32(5):929-940.
Previously we demonstrated that the heat shock transcription factor Hsf1 is indispensable for transformation of mammary epithelial cells by the Her2 oncogene. Since Hsf1 affects oncogene-induced senescence (OIS), these findings suggest that Hsf1 affects tumor initiation when OIS plays a role. Indeed, here we report that Hsf1 knockout suppressed mammary hyperplasia in Her2-expressing mice and reduced tumor emergence. On the other hand, Hsf1 expression increases with advanced breast cancer, indicating that there is an additional role of Hsf1 in tumor progression. We studied rare tumors that developed in Hsf1-knockout mice and found that these tumors grew slower than tumors in control animals and showed suppressed angiogenesis. Similarly, in the xenograft model, knockdown of Hsf1 suppressed angiogenesis, which was associated with suppression of the HIF-1 pathway. Suppression of HIF-1 was at the level of translation due to downregulation of the RNA-binding protein HuR. Importantly, besides HIF-1, HuR controls translation of other major regulators of cancer progression, many of which were suppressed in Hsf1-knockdown cells. Therefore, in addition to OIS, Hsf1 regulates the HuR–HIF-1 pathway, thus affecting both cancer initiation and progression.
PMCID: PMC3295200  PMID: 22215620
6.  Heat shock transcription factor HSF1 plays a critical role in HER2-induced cellular transformation and tumorigenesis 
Oncogene  2010;29(37):5204-5213.
The heat shock transcription factor HSF1 was recently demonstrated to play a key role in the development of tumors associated with activation of Ras or inactivation of p53. Here we show that HSF1 is required for cell transformation and tumorigenesis induced by HER2 oncogene responsible for aggressive breast tumors. Upon expression of HER2, untransformed human mammary epithelial cells MCF-10A underwent neoplastic transformation, formed foci in culture and tumors in nude mouse xenografts. However, expression of HER2 in MCF-10A cells with knockdown of HSF1 did not cause either foci formation or tumor growth in xenografts. The anti-tumorigenic effect of downregulation of HSF1 was associated with HER2-induced accumulation of the CDK inhibitor p21 and decrease of the mitotic regulator survivin, which resulted in growth inhibition and cell senescence. In fact, either knockout of p21 or overexpression of survivin alleviated these effects of HSF1 knockdown. Proliferation of certain human HER2-postitive breast cancer lines also requires HSF1, since its knockdown led to upregulation of p21 and/or drop of survivin, precipitating growth arrest. Similar effects were observed with a small molecular weight inhibitor of the heat shock response NZ28. Effects of HSF1 knockdown on growth arrest and senescence of HER2-expressing cells were associated with downregulation of Hsp72 and Hsp27. Therefore, HSF1 is critical for proliferation of HER2-expressing cells, most likely since it maintains levels of HSPs, which in turn control regulators of senescence p21 and survivin.
PMCID: PMC2940982  PMID: 20622894
HSF1; HER2; growth arrest; senescence; p21; survivin

Results 1-6 (6)