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.