p120-catenin in metastatic lobular breast cancer
Inactivation of E-cadherin leads to invasive lobular breast cancer (ILC) that metastasizes to the gastro-intestinal tract, lungs and bone marrow, reminiscent of the human condition. An emerging theme in literature is the role p120-catenin (p120) in cancer biology. p120 regulates recycling of E-cadherin and data from our laboratory and others have shown that p120 translocates to the cytosol and nucleus upon loss of E-cadherin. In the cytosol p120 functions as an oncogene regulating Rho signaling (see below) and Kaiso transcriptional repression (see Kaiso page).
We are unraveling the oncogenic signals that emanate from p120 in the cytosol, and performing genome-wide efforts combined with functional biology to identify p120/Kaiso targets in breast cancer. Based on these findings we are designing novel treatment regimens to target metastatic ILC.
We are unraveling the oncogenic signals that emanate from p120 in the cytosol, and performing genome-wide efforts combined with functional biology to identify p120/Kaiso targets in breast cancer. Based on these findings we are designing novel treatment regimens to target metastatic ILC.
LEFT Figure: Cytosolic p120 expression marks tumor progression of ILC.
Invasive E-cadherin mutant cells showing cytosol and nuclear p120 (black arrow), versus normal luminal mammary epithelial cells (White arrow).
RIGHT Figure: p120 controls ILC tumor growth and metastasis through Rho and Rock.
Doxycyclin (dox)-inducible Rock1 shRNA-expressing mouse ILC cells were transplanted into the 4th inguinal mammary gland of recipient mice and tumor volumes were measured longitudinally in the presence or absence of dox.
Invasive E-cadherin mutant cells showing cytosol and nuclear p120 (black arrow), versus normal luminal mammary epithelial cells (White arrow).
RIGHT Figure: p120 controls ILC tumor growth and metastasis through Rho and Rock.
Doxycyclin (dox)-inducible Rock1 shRNA-expressing mouse ILC cells were transplanted into the 4th inguinal mammary gland of recipient mice and tumor volumes were measured longitudinally in the presence or absence of dox.
Kaiso. Its regulation by p120 and consequences for tumor progression
Apart from its classical functions at the cell membrane, p120 can also regulate RhoGTPases when translocated to the cytosol (see p120 in lobular breast cancer page). Furthermore, it can interact with and relieve transcriptional repression of Kaiso, leading to expression of distinct target genes. Although controversy still covers the validity of the small number of targets that have been identified, alleged Kaiso target genes show overlap with Wnt signaling targets. As such it advocates Kaiso in a plethora of multiple developmental en pathological processes, including the regulation of tumor development and metastatic disease.
We have and are studying how Kaiso regulated gene transcription in cancer in a genome-wide manner. We initially focussed on the regulation of Kaiso by p120, but are also interested in p120-independent transcriptional regulation by Kaiso. We have published on how p120 reliefs Kaiso-dependent transcriptional repression of Wnt11 through its classical Kaiso Binding Sequence (KBS) TCCTGCNA, and the effect this has on tumor malignancy (see below).
We have and are studying how Kaiso regulated gene transcription in cancer in a genome-wide manner. We initially focussed on the regulation of Kaiso by p120, but are also interested in p120-independent transcriptional regulation by Kaiso. We have published on how p120 reliefs Kaiso-dependent transcriptional repression of Wnt11 through its classical Kaiso Binding Sequence (KBS) TCCTGCNA, and the effect this has on tumor malignancy (see below).
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Figure 1. E-cadherin mutant cells express nuclear p120
Immunofluorescence (IF) showing human and mouse ILC cells (E-cadherin mutant). In contrast, E-cadherin positive breast cancer cells (E-cadherin wild-type) do not express nuclear p120. Arrow heads depict nuclear p120 expression, size bars are 10µm. |
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Figure 2. How we identified candidate Kaiso target genes in ILC
The mILC Anoikis Resistance Transcriptome. To identify candidate Kaiso target genes upregulated in anchorage-independent conditions, eight independent mILC cell lines were cultured in adherent and suspension and subjected to genome-wide micro-array analysis. We identified 249 genes that were upregulated in mILC cells cultured under anchorage-independent conditions and termed this gene list the mILC Anoikis Resistance Transcriptome (ART). Subsequent transcription factor binding site (TFBS) promoter analysis of genes within the mILC ART revealed enrichment for the consensus binding sequence of Kaiso (Kaiso binding site: KBS). No enrichment for TCF/LEF binding sites was observed. Based on the presence of KBS sequences in the promoter regions of genes within the mILC ART we identified 29 candidate Kaiso target genes including Wnt11. The p-values reported in this figure are the result of initial testing for the KBS and TCF/LEF consensus sites. |
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