Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance

Schackmann, Ron C.J.; Amersfoort, Miranda van; Haarhuis, Judith H.I.; Vlug, Eva J.; Halim, Vincentius A.; Roodhart, Jeanine M.L.; Vermaat, Joost S.P.; Voest, Emile E.; Groep, Petra van der; Diest, Paul J. van; Jonkers, Jos; Derksen, Patrick W.B.

doi:10.1172/jci41695

Cited by 121 publications

(191 citation statements)

References 48 publications

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“…42,43 Recent studies indicated that BH3-mimetics can be used to treat nonlymphoid cancers but mostly in combination with oestrogen antagonists, proteasome inhibitors, specific PI3K-mTOR inhibitors or chemotherapy. 24,[44][45][46][47][48][49] As previous findings from our laboratory demonstrated that E-cadherin-negative lobular breast cancer depends on p120-catenin-mediated activation of RhoA, Rock and subsequent actomyosin contraction, 26 we anticipate that dual inhibition of these pathways might be successful in E-cadherin-negative cancers that are not driven by oncogenic activation of GFR pathways. Although we do not yet know whether RhoA-Rock signals converge onto the GFR-AKT-FOXO axis in the regulation of anoikis resistance, the fact that FOXO expression had no effect on survival of B-RAF/KRAS-mutated MDA-MB-231 cells seems to be in line with this assumption.…”

Section: Discussionmentioning

confidence: 83%

“…Under these conditions, the non-metastatic mouse mammary carcinoma cell line Trp53 Δ/Δ -4 and human MCF7 underwent anoikis as previously demonstrated. 20,26 In contrast, mouse and human E-cadherin-negative mILC1 and MDA-MB-231 cells were anoikis resistant (Figures 1a and b).…”

Section: Resultsmentioning

confidence: 96%

“…For longitudinal tumour growth and dissemination experiments, 10 000 mILC1 cells were transplanted in the fourth inguinal mouse mammary gland of Nude-recipient mice as described previously. 26 Primary tumours were allowed to develop to a volume of 100 mm 3 at which point expression of BMF was induced by feeding Dox-containing chow (Ssniff, Soest, Germany). Alternatively, BMF expression was induced when lung metastasis were detected using BLI of the thorax (42 × 10 3 photons/s/cm 2 /sr).…”

Section: Materials and Methods Cell Lines Mouse Breast Cancer Cell Lmentioning

confidence: 99%

“…Tumour volumes and lung metastases were followed in time as described using a Biospace ϕ imager (Nesles la Vallée, France). 26 All animal experiments were approved by the Utrecht University Animal Experimental Committee (DEC-ABC no. 2012.III.05.044).…”

Section: Materials and Methods Cell Lines Mouse Breast Cancer Cell Lmentioning

confidence: 99%

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Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

et al. 2016

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Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.

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Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 96%

Section: Materials and Methods Cell Lines Mouse Breast Cancer Cell Lmentioning

confidence: 99%

Section: Materials and Methods Cell Lines Mouse Breast Cancer Cell Lmentioning

confidence: 99%

See 2 more Smart Citations

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

et al. 2016

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“…Alternatively, cytosolic p120catenin may activate Rho by inhibiting the antagonist of Rho/ROCK signalling Myosin phosphatase Rho-interacting protein (Mrip), in an invasive lobular carcinoma mouse model [110] (figure 4). Activation of Rho and ROCK signalling by cytosolic p120catenin can influence cell migration and invasion, and promote anchorage independent survival of Ecadherin-deficient cancer cells [110]. p120catenin can also act downstream of Src and Rac1 to suppress the RhoA-ROCK signalling pathway, highlighting the role of p120catenin in the crucial interplay between Rac and Rho signalling.…”

Section: (B) Cytosolic P120catenin Interacts With and Modulates Rho-gmentioning

confidence: 99%

p120catenin alteration in cancer and its role in tumour invasion

Péglion

Etienne-Manneville

2013

Phil. Trans. R. Soc. B

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Since its discovery in 1989 as a substrate of the Src oncogene, p120catenin has been revealed as an important player in cancer initiation and tumour dissemination. p120catenin regulates a wide range of cellular processes such as cell–cell adhesion, cell polarity and cell proliferation and plays a pivotal role in morphogenesis, inflammation and innate immunity. The pleiotropic effects of p120catenin rely on its interactions with numerous partners such as classical cadherins at the plasma membrane, Rho-GTPases and microtubules in the cytosol and transcriptional modulators in the nucleus. Alterations of p120catenin in cancer not only concern its expression level but also its intracellular localization and can lead to both pro-invasive and anti-invasive effects. This review focuses on the p120catenin-mediated pathways involved in cell migration and invasion and discusses the potential consequences of major cancer-related p120catenin alterations with respect to tumour spread.

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Microenvironment‐induced restoration of cohesive growth associated with focal activation of P‐cadherin expression in lobular breast carcinoma metastatic to the colon

Gronewold,

Grote,

Bartels

et al. 2024

The Journal of Pathology CR

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Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E‐cadherin loss. Focal activation of P‐cadherin expression in tumor cells that are deficient for E‐cadherin occurs in a subset of ILCs. Switching from an E‐cadherin deficient to P‐cadherin proficient status (EPS) partially restores cell–cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52‐year‐old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E‐cadherin and P‐cadherin. CDH1/E‐cadherin mutations were determined by next‐generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a CDH1/E‐cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E‐cadherin‐negative and P‐cadherin‐negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter‐cryptal ILC cells switched to a P‐cadherin‐positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment‐induced EPS and conversion to cohesive growth.

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Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance

Cited by 121 publications

References 48 publications

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

p120catenin alteration in cancer and its role in tumour invasion

Microenvironment‐induced restoration of cohesive growth associated with focal activation of P‐cadherin expression in lobular breast carcinoma metastatic to the colon

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