Therapeutic targeting of integrin αvβ6 in breast cancer

Kate M Moore; Gareth J Thomas; Stephen W Duffy; Jane Warwick; Rhian Gabe; Patrick Chou; Ian O Ellis; Andrew R Green; Syed Haider; Kellie Brouilette; Antonio Saha; Sabari Vallath; Rebecca Bowen; Claude Chelala; Diana Eccles; William J Tapper; Alastair M Thompson; Phillip Quinlan; Lee Jordan; Cheryl Gillett; Adam Brentnall; Shelia Violette; Paul H Weinreb; Jane Kendrew; Simon T Barry; Ian R Hart; J Louise Jones; John F Marshall

doi:10.1093/jnci/dju169

Therapeutic targeting of integrin αvβ6 in breast cancer

Kate M Moore, Gareth J Thomas, Stephen W Duffy, Jane Warwick, Rhian Gabe, Patrick Chou, Ian O Ellis, Andrew R Green, Syed Haider, Kellie Brouilette, Antonio Saha, Sabari Vallath, Rebecca Bowen, Claude Chelala, Diana Eccles, William J Tapper, Alastair M Thompson, Phillip Quinlan, Lee Jordan, Cheryl GillettAdam Brentnall, Shelia Violette, Paul H Weinreb, Jane Kendrew, Simon T Barry, Ian R Hart, J Louise Jones, John F Marshall

The Hull York Medical School

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

Abstract

BACKGROUND: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.

METHODS: Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.

RESULTS: High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.

CONCLUSIONS: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.

Original language	English
Number of pages	14
Journal	Journal of the National Cancer Institute
Volume	106
Issue number	8
DOIs	https://doi.org/10.1093/jnci/dju169
Publication status	Published - 13 Aug 2014

Bibliographical note

Keywords

Animals
Antibodies, Monoclonal, Humanized
Antigens, Neoplasm
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Breast Neoplasms
Female
Flow Cytometry
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Immunohistochemistry
Integrins
Kaplan-Meier Estimate
Mice
Mice, SCID
Molecular Targeted Therapy
Receptor, ErbB-2
Treatment Outcome
Xenograft Model Antitumor Assays

Access to Document

10.1093/jnci/dju169

Cite this

Moore, K. M., Thomas, G. J., Duffy, S. W., Warwick, J., Gabe, R., Chou, P., Ellis, I. O., Green, A. R., Haider, S., Brouilette, K., Saha, A., Vallath, S., Bowen, R., Chelala, C., Eccles, D., Tapper, W. J., Thompson, A. M., Quinlan, P., Jordan, L., ... Marshall, J. F. (2014). Therapeutic targeting of integrin αvβ6 in breast cancer. Journal of the National Cancer Institute, 106(8). https://doi.org/10.1093/jnci/dju169

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title = "Therapeutic targeting of integrin αvβ6 in breast cancer",

abstract = "BACKGROUND: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.",

keywords = "Animals, Antibodies, Monoclonal, Humanized, Antigens, Neoplasm, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Immunohistochemistry, Integrins, Kaplan-Meier Estimate, Mice, Mice, SCID, Molecular Targeted Therapy, Receptor, ErbB-2, Treatment Outcome, Xenograft Model Antitumor Assays",

author = "Moore, {Kate M} and Thomas, {Gareth J} and Duffy, {Stephen W} and Jane Warwick and Rhian Gabe and Patrick Chou and Ellis, {Ian O} and Green, {Andrew R} and Syed Haider and Kellie Brouilette and Antonio Saha and Sabari Vallath and Rebecca Bowen and Claude Chelala and Diana Eccles and Tapper, {William J} and Thompson, {Alastair M} and Phillip Quinlan and Lee Jordan and Cheryl Gillett and Adam Brentnall and Shelia Violette and Weinreb, {Paul H} and Jane Kendrew and Barry, {Simon T} and Hart, {Ian R} and Jones, {J Louise} and Marshall, {John F}",

note = "{\textcopyright} The Author 2014. Published by Oxford University Press.",

year = "2014",

month = aug,

day = "13",

doi = "10.1093/jnci/dju169",

language = "English",

volume = "106",

journal = "Journal of the National Cancer Institute",

issn = "1460-2105",

publisher = "Oxford University Press",

number = "8",

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Moore, KM, Thomas, GJ, Duffy, SW, Warwick, J, Gabe, R, Chou, P, Ellis, IO, Green, AR, Haider, S, Brouilette, K, Saha, A, Vallath, S, Bowen, R, Chelala, C, Eccles, D, Tapper, WJ, Thompson, AM, Quinlan, P, Jordan, L, Gillett, C, Brentnall, A, Violette, S, Weinreb, PH, Kendrew, J, Barry, ST, Hart, IR, Jones, JL & Marshall, JF 2014, 'Therapeutic targeting of integrin αvβ6 in breast cancer', Journal of the National Cancer Institute, vol. 106, no. 8. https://doi.org/10.1093/jnci/dju169

TY - JOUR

T1 - Therapeutic targeting of integrin αvβ6 in breast cancer

AU - Moore, Kate M

AU - Thomas, Gareth J

AU - Duffy, Stephen W

AU - Warwick, Jane

AU - Gabe, Rhian

AU - Chou, Patrick

AU - Ellis, Ian O

AU - Green, Andrew R

AU - Haider, Syed

AU - Brouilette, Kellie

AU - Saha, Antonio

AU - Vallath, Sabari

AU - Bowen, Rebecca

AU - Chelala, Claude

AU - Eccles, Diana

AU - Tapper, William J

AU - Thompson, Alastair M

AU - Quinlan, Phillip

AU - Jordan, Lee

AU - Gillett, Cheryl

AU - Brentnall, Adam

AU - Violette, Shelia

AU - Weinreb, Paul H

AU - Kendrew, Jane

AU - Barry, Simon T

AU - Hart, Ian R

AU - Jones, J Louise

AU - Marshall, John F

N1 - © The Author 2014. Published by Oxford University Press.

PY - 2014/8/13

Y1 - 2014/8/13

N2 - BACKGROUND: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.

AB - BACKGROUND: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.METHODS: Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.RESULTS: High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.CONCLUSIONS: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.

KW - Animals

KW - Antibodies, Monoclonal, Humanized

KW - Antigens, Neoplasm

KW - Antineoplastic Agents

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Breast Neoplasms

KW - Female

KW - Flow Cytometry

KW - Gene Expression Regulation, Neoplastic

KW - Gene Knockdown Techniques

KW - Humans

KW - Immunohistochemistry

KW - Integrins

KW - Kaplan-Meier Estimate

KW - Mice

KW - Mice, SCID

KW - Molecular Targeted Therapy

KW - Receptor, ErbB-2

KW - Treatment Outcome

KW - Xenograft Model Antitumor Assays

U2 - 10.1093/jnci/dju169

DO - 10.1093/jnci/dju169

M3 - Article

C2 - 24974129

SN - 1460-2105

VL - 106

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 8

ER -