Loss of the Par3 Polarity Protein Promotes Breast Tumorigenesis and Metastasis

McCaffrey, Luke; Montalbano, JoAnne; Mihai, Constantina; Macara, Ian G.

doi:10.1016/j.ccr.2012.10.003

Cited by 196 publications

(198 citation statements)

References 52 publications

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“…Par3 knockout led to enhanced breast tumorigenesis and metastasis in mice, whereas Par3 exerted cell context-dependent oncogenic or tumor-suppressing roles in skin cancers. 36,37 It is possible that PAR3 is also responsible for the positive effects of Shp2 on prostate cancer cell proliferation, sphere formation and in vivo tumor formation, besides its function in the regulation of cell polarity. On the other hand, considering the role of Shp2 in Ras and other signaling pathways, we do not exclude other signaling downstream effectors for the positive role of Shp2 in prostate tumors.…”

Section: Discussionmentioning

confidence: 99%

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Zhang

Zhao

et al. 2015

Oncogene

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Epithelial-to-mesenchymal transition (EMT), marked by the dissolution of cell-cell junctions, loss of cell polarity and increased cell motility, is one of the essential steps for prostate cancer metastasis. However, the underlying mechanism has not been fully explored. We report in this study that Shp2 is upregulated in prostate cancers and is associated with a poor disease outcome, namely tumor metastasis and shortened patient survival. Overexpression of wild-type Shp2 or an oncogenic Shp2 mutant leads to increased prostate cancer cell proliferation, colony and sphere formation, and in vivo tumor formation. Opposite effects are seen in Shp2-knockdown cells. Moreover, Shp2 promotes in vitro migration and in vivo metastasis of prostatic tumor cells. Mechanistically, Shp2 interacts with PAR3 (partitioning-defective 3) via its Src homology-2 domain. Ectopic expression of Shp2 attenuates the phosphorylation of PAR3 and the formation of the PAR3/PAR6/atypical protein kinase C polarity protein complex, resulting in disrupted cell polarity, dysregulated cell-cell junctions and increased EMT. These findings provide a novel mechanism by which oncogenic signal-transduction molecules regulate cell polarity and induction of EMT.

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Section: Discussionmentioning

confidence: 99%

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Zhang

Zhao

et al. 2015

Oncogene

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“…Silencing of Stat3 blocked lung colonization and expression of a constitutively active Stat3 mutant stimulated invasive behaviour even in the presence of Par3. Strikingly, human breast cancers frequently exhibit loss of Par3 expression, which correlates closely with increased aPKC and Stat3 phosphorylation [23]. This pathway seems to depend on oncogenic activation, because although loss of Par3 is in itself sufficient to cause mislocalization of aPKC, the kinase is not activated except in transformed cells.…”

Section: Par Polarity Proteins In Cancer Progressionmentioning

confidence: 99%

Cell polarity in morphogenesis and metastasis

Macara

McCaffrey

2013

Phil. Trans. R. Soc. B

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Most human cancers arise either from epithelial cells or their progenitors. Epithelial cells possess a distinctive apical–basal polarity and loss of polarity is frequently assumed to be a common feature of cancer progression. In particular, cancer cell dissemination to ectopic sites, and metastatic growth at those sites, is often considered to require a mesenchymal transition in which the transformed epithelial cells lose their apical–basal polarity. However, many cancers retain epithelial characteristics, and until recently there has been little conclusive evidence for an involvement of the cell polarity machinery in tumour growth and metastasis. In this article, we discuss evidence that polarity proteins can be potent invasion suppressors but that loss of epithelial character is not essential either for tumour growth and invasion, or metastatic colonization.

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“…This approach showed that sole Par3 depletion inhibits regrowth of the mammary gland due to increased aporptosis (4). Based on this, loss of Par3 is unlikely to be a cancer initiating event.…”

Section: Cells and In Order To Speak Of A True Cancer-initiation Is mentioning

confidence: 96%

“…Based on this, loss of Par3 is unlikely to be a cancer initiating event. However, loss of Par3 synergized with oncogenes like Ras or ErbB2 to promote tumorigenesis (4,5), thus placing loss of Par3 as a tumor-promoting event.…”

Section: Cells and In Order To Speak Of A True Cancer-initiation Is mentioning

confidence: 99%

Endomembrane control of cell polarity: Relevance to cancer

Baschieri

Farhan

2015

Small GTPases

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The role of polarity in cancer is an emerging research area and loss of polarity is widely considered an important event in cancer. Among the polarity regulating molecules, the small GTPase Cdc42 was extensively studied. Most attention was given to Cdc42 signaling at the plasma membrane, but whether and how Cdc42 is regulated at endomembranes remained poorly understood. Moreover, whether the endomembrane pool of Cdc42 is of any relevance to cell polarity was unknown. In our recent work, we identified a complex between the Golgi matrix protein GM130 and RasGRF and showed that it is responsible for regulating the Golgi pool of Cdc42, but had no effect on the plasma membrane pool of Cdc42. Depletion of GM130 disrupted apico-basal polarity as well as front-rear polarity, indicating that the spatial pool of Cdc42 is functionally relevant. The biomedical relevance of this finding was supported by the observation than GM130 is progressively lost in colorectal cancer. These findings support a role of the endomembrane pool of Cdc42 in cell polarity and point to a potential role of alterations of this pool in cancer.

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Loss of the Par3 Polarity Protein Promotes Breast Tumorigenesis and Metastasis

Cited by 196 publications

References 52 publications

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition

Cell polarity in morphogenesis and metastasis

Endomembrane control of cell polarity: Relevance to cancer

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