Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer

Gabriele Corda; Gianluca Sala; Rossano Lattanzio; Manuela Iezzi; Michele Sallese; Giorgia Fragassi; Alessia Lamolinara; Hasan Mirza; Daniela Barcaroli; Sibylle Ermler; Elisabete Silva; Hemad Yasaei; Robert F. Newbold; Paola Vagnarelli; Marcella Mottolese; Pier Giorgio Natali; Letizia Perracchio; Jelmar Quist; Anita Grigoriadis; Pierfrancesco Marra; Andrew N. Tutt; Mauro Piantelli; Stefano Iacobelli; Vincenzo De Laurenzi; Arturo Sala

doi:10.1002/path.4841

Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer

Gabriele Corda, Gianluca Sala, Rossano Lattanzio, Manuela Iezzi, Michele Sallese, Giorgia Fragassi, Alessia Lamolinara, Hasan Mirza, Daniela Barcaroli, Sibylle Ermler, Elisabete Silva, Hemad Yasaei, Robert F. Newbold, Paola Vagnarelli, Marcella Mottolese, Pier Giorgio Natali, Letizia Perracchio, Jelmar Quist, Anita Grigoriadis, Pierfrancesco MarraAndrew N. Tutt, Mauro Piantelli, Stefano Iacobelli, Vincenzo De Laurenzi^*, Arturo Sala

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

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Abstract

Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC.

Original language	English
Pages (from-to)	350-361
Number of pages	12
Journal	Journal of pathology
Volume	241
Issue number	3
Early online date	9 Nov 2016
DOIs	https://doi.org/10.1002/path.4841
Publication status	Published - 1 Feb 2017

Keywords

actin cytoskeleton
metastasis
mouse model
Wnt signalling
xenograft

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Corda, G., Sala, G., Lattanzio, R., Iezzi, M., Sallese, M., Fragassi, G., Lamolinara, A., Mirza, H., Barcaroli, D., Ermler, S., Silva, E., Yasaei, H., Newbold, R. F., Vagnarelli, P., Mottolese, M., Natali, P. G., Perracchio, L., Quist, J., Grigoriadis, A., ... Sala, A. (2017). Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer. Journal of pathology, 241(3), 350-361. https://doi.org/10.1002/path.4841

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title = "Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer",

abstract = "Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC.",

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author = "Gabriele Corda and Gianluca Sala and Rossano Lattanzio and Manuela Iezzi and Michele Sallese and Giorgia Fragassi and Alessia Lamolinara and Hasan Mirza and Daniela Barcaroli and Sibylle Ermler and Elisabete Silva and Hemad Yasaei and Newbold, {Robert F.} and Paola Vagnarelli and Marcella Mottolese and Natali, {Pier Giorgio} and Letizia Perracchio and Jelmar Quist and Anita Grigoriadis and Pierfrancesco Marra and Tutt, {Andrew N.} and Mauro Piantelli and Stefano Iacobelli and {De Laurenzi}, Vincenzo and Arturo Sala",

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Corda, G, Sala, G, Lattanzio, R, Iezzi, M, Sallese, M, Fragassi, G, Lamolinara, A, Mirza, H, Barcaroli, D, Ermler, S, Silva, E, Yasaei, H, Newbold, RF, Vagnarelli, P, Mottolese, M, Natali, PG, Perracchio, L, Quist, J , Grigoriadis, A, Marra, P, Tutt, AN, Piantelli, M, Iacobelli, S, De Laurenzi, V & Sala, A 2017, 'Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer', Journal of pathology, vol. 241, no. 3, pp. 350-361. https://doi.org/10.1002/path.4841

TY - JOUR

T1 - Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer

AU - Corda, Gabriele

AU - Sala, Gianluca

AU - Lattanzio, Rossano

AU - Iezzi, Manuela

AU - Sallese, Michele

AU - Fragassi, Giorgia

AU - Lamolinara, Alessia

AU - Mirza, Hasan

AU - Barcaroli, Daniela

AU - Ermler, Sibylle

AU - Silva, Elisabete

AU - Yasaei, Hemad

AU - Newbold, Robert F.

AU - Vagnarelli, Paola

AU - Mottolese, Marcella

AU - Natali, Pier Giorgio

AU - Perracchio, Letizia

AU - Quist, Jelmar

AU - Grigoriadis, Anita

AU - Marra, Pierfrancesco

AU - Tutt, Andrew N.

AU - Piantelli, Mauro

AU - Iacobelli, Stefano

AU - De Laurenzi, Vincenzo

AU - Sala, Arturo

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC.

AB - Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6–fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC.

KW - actin cytoskeleton

KW - metastasis

KW - mouse model

KW - Wnt signalling

KW - xenograft

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DO - 10.1002/path.4841

M3 - Article

AN - SCOPUS:85009183767

SN - 0022-3417

VL - 241

SP - 350

EP - 361

JO - Journal of pathology

JF - Journal of pathology

IS - 3

ER -

Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer

Abstract

Keywords

UN SDGs

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