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PMID: 19047149 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor.

Cancer research ·Vol. 68 ·No. 23 ·2008-12-01 ·Pages 9712-22

Saxena NK, Taliaferro-Smith L, Knight BB, Merlin D, Anania FA, O'Regan RM, Sharma D

Abstract

Obesity is an independent risk factor for breast cancer, and obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Obesity, as associated with metabolic syndrome, results in an increase in circulating insulin-like growth factor (IGF), which acts as a mitogen. In addition, higher plasma level of adipocytokine leptin is associated with obesity. In the present study, we show that cotreatment with leptin and IGF-I significantly increases proliferation as well as invasion and migration of breast cancer cells. We found a novel bidirectional crosstalk between leptin and IGF-I signaling; IGF-I induced phosphorylation of leptin receptor (Ob-Rb) and leptin induced phosphorylation of IGF-I receptor (IGF-IR), whereas cotreatment induced synergistic phosphorylation and association of Ob-Rb and IGF-IR along with activation of downstream effectors, Akt and extracellular signal-regulated kinase. Leptin increased phosphorylation of IGF signaling molecules insulin-receptor substrate (IRS)-1 and IRS-2. Interestingly, we found that leptin and IGF-I cotreatment synergistically transactivated epidermal growth factor receptor (EGFR), depending on the proteolytic release of EGFR ligands, as the broad-spectrum matrix metalloproteinase inhibitor GM6001 could inhibit this effect. Using clinically relevant EGFR inhibitors, erlotinib and lapatinib, we found that inhibition of EGFR activation effectively inhibited leptin- and IGF-I-induced invasion and migration of breast cancer cells. Taken together, these data suggest a novel bidirectional crosstalk between leptin and IGF-I signaling that transactivates EGFR and promotes the metastatic properties as well as invasion and migration of breast cancer cells. Our findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the procancerous effects of leptin and IGF-I in breast cancers.

MeSH Terms
Breast Neoplasms/genetics,metabolism,pathology Cell Growth Processes/drug effects Cell Line, Tumor Cell Movement/drug effects,physiology Drug Synergism ErbB Receptors/antagonists & inhibitors,genetics,metabolism Erlotinib Hydrochloride Humans Insulin-Like Growth Factor I/antagonists & inhibitors,metabolism,pharmacology Lapatinib Leptin/antagonists & inhibitors,metabolism,pharmacology Neoplasm Invasiveness Quinazolines/pharmacology Receptor Cross-Talk Receptor, IGF Type 1/metabolism Receptors, Leptin/metabolism Signal Transduction Transcriptional Activation
Chemicals
Leptin Quinazolines Receptors, Leptin leptin receptor, human Lapatinib Insulin-Like Growth Factor I Erlotinib Hydrochloride ErbB Receptors Receptor, IGF Type 1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Saxena Neeraj K
Department of Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA. [email protected]
Taliaferro-Smith LaTonia
Knight Brandi B
Merlin Didier
Anania Frank A
O'Regan Ruth M
Sharma Dipali
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-1952
Email
[email protected]
Published
2008-12-01
Pages
9712-22
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC3180854
Subset
IM
Grants
NIDDK NIH HHS · R01DK075397 · United States
NCI NIH HHS · R01 CA131294 · United States
NIDDK NIH HHS · R01DK071594 · United States
NIDDK NIH HHS · R01 DK071594 · United States
NIDDK NIH HHS · R03 DK089130 · United States
NIDDK NIH HHS · K01 DK076742 · United States
NIDDK NIH HHS · R01DK061941 · United States
NIDDK NIH HHS · R01 DK062092 · United States
NIDDK NIH HHS · R01 DK061941 · United States
NIDDK NIH HHS · K01 DK077137 · United States
NIDDK NIH HHS · R24 DK064399 · United States
NIDDK NIH HHS · K01DK076742 · United States
NIDDK NIH HHS · DK064399 · United States
NIDDK NIH HHS · R01DK062092 · United States
NIDDK NIH HHS · R01 DK075397 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-08-1952 PMC Full Text View journal details
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