Functional Redundancy between β1 and β3 Integrin in Activating the IR/Akt/mTORC1 Signaling Axis to Promote ErbB2-Driven Breast Cancer.
Integrin receptors coordinate cell adhesion to the extracellular matrix (ECM) to facilitate many cellular processes during malignant transformation. Despite their pro-tumorigenic roles, therapies targeting integrins remain limited. Here, we provide genetic evidence supporting a functional redundancy between β1 and β3 integrin during breast cancer progression. Although ablation of β1 or β3 integrin alone has limited effects on ErbB2-driven mammary tumorigenesis, deletion of both receptors resulted in a significant delay in tumor onset with a corresponding impairment in lung metastasis. Mechanistically, stiff ECM cooperates with integrin receptors to recruit insulin receptors (IRs) to focal adhesion through the formation of integrin/IR complexes, thereby preventing their lysosomal degradation. β1/β3 integrin-deficient tumors that eventually emerged exhibit impaired Akt/mTORC1 activity. Murine and human breast cancers exhibiting enhanced integrin-dependent activity also display elevated IR/Akt/mTORC1 signaling activity. Together, these observations argue that integrin/IR crosstalk transduces mechanical cues from the tumor microenvironment to promote ErbB2-dependent breast cancer progression.
Pubmed ID: 31618629 RIS Download
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Antibodies used in this publication
- IRDye 800CW Donkey anti-Rabbit IgG (RRID:AB_2715510)
- S6 Ribosomal Protein (54D2) Mouse mAb (RRID:AB_2238583)
- Rat monoclonal anti-mouse endothelial cell marker CD31 (PECAM-1) (RRID:AB_2631039)
- Anti-LAMP1 antibody - Lysosome Marker (RRID:AB_775978)
- GAPDH Antibody (RRID:AB_10001458)
- Rabbit Anti-Green Fluorescent Protein (GFP) Polyclonal Antibody, Unconjugated (RRID:AB_221570)
- Anti-Integrin beta1, activated, clone HUTS-4, Azide Free (RRID:AB_2233964)
- Phospho-HER2/ErbB2 (Tyr1221/1222) (6B12) Rabbit mAb (RRID:AB_490899)
- Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (20G11) Rabbit mAb (RRID:AB_331772)
- Phospho-FAK (Tyr397) Polyclonal Antibody (RRID:AB_2533701)
- c-erbB-2, c-neu (RRID:AB_2099416)
- HA-Tag (C29F4) Rabbit mAb (RRID:AB_1549585)
- Insulin Receptor β (4B8) Rabbit mAb (RRID:AB_2280448)
- Mouse Anti-CD29 Monoclonal Antibody, Unconjugated, Clone 18 (RRID:AB_397840)
- Anti-phospho-Insulin Receptor (Tyr 1322), clone 21G12 (RRID:AB_805368)
- Anti-Rat IgG (H+L), mouse adsorbed, made in rabbit (RRID:AB_10015300)
- Integrin beta 1 antibody [3B6] (RRID:AB_11127654)
- HA-Tag (6E2) Mouse mAb (RRID:AB_10691311)
- Phospho-IGF-I Receptor beta (Tyr1135/1136)/Insulin Receptor beta (Tyr1150/1151) (19H7) Rabbit mAb (RRID:AB_331253)
- Phospho-4E-BP1 (Ser65) Antibody (RRID:AB_330947)
- Anti-Puromycin Antibody, clone 12D10 (RRID:AB_2566826)
- Phospho-IGF-I Receptor beta (Tyr1131)/Insulin Receptor beta (Tyr1146) Antibody (RRID:AB_331578)
- Anti-β-Actin Antibody (RRID:AB_476744)
- 4E-BP1 Antibody (RRID:AB_331692)
- Anti-Akt Substrate, phsopho (Ser / Thr) Antibody, Unconjugated (RRID:AB_330302)
- Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb (RRID:AB_916156)
- Phospho-S6 Ribosomal Protein (Ser240/244) (D68F8) XP Rabbit mAb (RRID:AB_10694233)
- Anti-4E-BP1, phospho (Thr37 / Thr46) Monoclonal Antibody (RRID:AB_560835)
- Phospho-Akt (Thr308) (244F9) Rabbit mAb (RRID:AB_331163)
- Phospho-Akt (Ser473) Antibody (RRID:AB_329825)
- p44/42 MAPK (Erk1/2) Antibody (RRID:AB_330744)
- Akt1/2 (N-19) (RRID:AB_671713)
- CD 29, Integrin beta 1 (RRID:AB_2128202)
- Phospho-Myosin Light Chain 2 (Ser19) Antibody (RRID:AB_330248)
- Phospho-Paxillin (Tyr118) Antibody (RRID:AB_2174466)
- Anti-Vinculin, clone VIIF9 (7F9) (RRID:AB_2304338)
- Integrin β3 (D7X3P) XP® Rabbit mAb (RRID:AB_2798136)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- Integrin β1 (D6S1W) Rabbit mAb (RRID:AB_2799067)
- BrdU (Bu20a) Mouse mAb (RRID:AB_10548898)
Associated grants
- Agency: CIHR, Canada
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View all literature mentionsIRDye 800CW Donkey anti-Rabbit IgG (antibody)
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This monoclonal targets S6 Ribosomal Protein (54D2) Mouse mAb
View all literature mentionsRat monoclonal anti-mouse endothelial cell marker CD31 (PECAM-1) (antibody)
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This monoclonal targets CD31
View all literature mentionsAnti-LAMP1 antibody - Lysosome Marker (antibody)
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This polyclonal targets LAMP1
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This polyclonal targets GAPDH
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This polyclonal targets Green Fluorescent Protein (GFP)
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RRID:AB_2233964
This monoclonal targets Integrin beta1 activated clone HUTS-4 Azide Free
View all literature mentionsPhospho-HER2/ErbB2 (Tyr1221/1222) (6B12) Rabbit mAb (antibody)
RRID:AB_490899
This monoclonal targets Monoclonal antibodies are produced by immunizing rabbits with a synthetic phosphopeptide (KLH-coupled) corresponding to residues surrounding tyrosines 1221/1222 of human ErbB2 protein.
View all literature mentionsPhospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (20G11) Rabbit mAb (antibody)
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This monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
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RRID:AB_2533701
This polyclonal targets Phospho-FAK (Tyr397)
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This monoclonal targets Generated from carboxyl terminus of human c-neu gene product
View all literature mentionsHA-Tag (C29F4) Rabbit mAb (antibody)
RRID:AB_1549585
This monoclonal targets HA-Tag
View all literature mentionsInsulin Receptor β (4B8) Rabbit mAb (antibody)
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This recombinant monoclonal targets Insulin Receptor beta
View all literature mentionsMouse Anti-CD29 Monoclonal Antibody, Unconjugated, Clone 18 (antibody)
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This monoclonal targets CD29 (Integrin β1 chain)
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This monoclonal targets phospho-Insulin Receptor (Tyr 1322) clone 21G12
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View all literature mentionsIntegrin beta 1 antibody [3B6] (antibody)
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This monoclonal targets Integrin beta 1 antibody [3B6]
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This monoclonal targets HA-Tag
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RRID:AB_331253
This monoclonal targets Phospho-IGF-I Receptor beta (Tyr1135/1136)/Insulin Receptor beta (Tyr1150/1151) (19H7) Rabbit mAb
View all literature mentionsPhospho-4E-BP1 (Ser65) Antibody (antibody)
RRID:AB_330947
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This monoclonal targets Puromycin from Streptomyces alboniger
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RRID:AB_331578
This polyclonal targets Phospho-IGF-I Receptor beta (Tyr1131)/Insulin Receptor beta (Tyr1146)
View all literature mentionsAnti-β-Actin Antibody (antibody)
RRID:AB_476744
This monoclonal targets slightly modified β-cytoplasmic actin N-terminal peptide, Ac-Asp-Asp-Asp-Ile-Ala-Ala-Leu-Val-Ile-Asp-Asn-Gly-Ser-Gly-Lys, conjugated to KLH
View all literature mentions4E-BP1 Antibody (antibody)
RRID:AB_331692
This polyclonal targets 4E-BP1
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RRID:AB_330302
This unknown targets Akt Substrate, phsopho (Ser / Thr)
View all literature mentionsPhospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb (antibody)
RRID:AB_916156
This monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsPhospho-S6 Ribosomal Protein (Ser240/244) (D68F8) XP Rabbit mAb (antibody)
RRID:AB_10694233
This monoclonal targets Phospho-S6 Ribosomal Protein (Ser240/244) (D68F8) XP Rabbit mAb
View all literature mentionsAnti-4E-BP1, phospho (Thr37 / Thr46) Monoclonal Antibody (antibody)
RRID:AB_560835
This monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)
View all literature mentionsPhospho-Akt (Thr308) (244F9) Rabbit mAb (antibody)
RRID:AB_331163
This monoclonal targets Phospho-Akt (Thr308) (244F9) Rabbit mAb
View all literature mentionsPhospho-Akt (Ser473) Antibody (antibody)
RRID:AB_329825
This polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsp44/42 MAPK (Erk1/2) Antibody (antibody)
RRID:AB_330744
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsAkt1/2 (N-19) (antibody)
RRID:AB_671713
This polyclonal targets Akt1/2 (N-19)
View all literature mentionsCD 29, Integrin beta 1 (antibody)
RRID:AB_2128202
This monoclonal targets ND
View all literature mentionsPhospho-Myosin Light Chain 2 (Ser19) Antibody (antibody)
RRID:AB_330248
This polyclonal targets Phospho-Myosin Light Chain 2 (Ser19)
View all literature mentionsPhospho-Paxillin (Tyr118) Antibody (antibody)
RRID:AB_2174466
This polyclonal targets Phospho-Paxillin (Tyr118)
View all literature mentionsAnti-Vinculin, clone VIIF9 (7F9) (antibody)
RRID:AB_2304338
This monoclonal targets VCL
View all literature mentionsIntegrin β3 (D7X3P) XP® Rabbit mAb (antibody)
RRID:AB_2798136
This monoclonal targets ITGB3
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsIntegrin β1 (D6S1W) Rabbit mAb (antibody)
RRID:AB_2799067
This monoclonal targets ITGB1
View all literature mentionsBrdU (Bu20a) Mouse mAb (antibody)
RRID:AB_10548898
This monoclonal targets BrdU (Bu20a) Mouse mAb
View all literature mentionsC57BL/6-Itgb3tm1.1Wlbcr/J (organism)
RRID:IMSR_JAX:028232
Mus musculus with name C57BL/6-Itgb3tm1.1Wlbcr/J from IMSR.
View all literature mentionsB6;129X1-Itgb1tm1Mll/AjkJ (organism)
RRID:IMSR_JAX:029354
Mus musculus with name B6;129X1-Itgb1tm1Mll/AjkJ from IMSR.
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