Breast cancer is one of the most common
malignancies and a major cause of
cancer death among women worldwide. The high mortality rate associated with
breast cancer is mainly due to a propensity of the
tumor to metastasize, even if small or undetectable. Given the relevant role of
leptin in
breast cancer growth and
metastasis, novel strategies to counteract
biological effects of this
obesity-linked
cytokine are warranted. Recently, we demonstrated that in MDA-MB-231
breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1/2 and STAT3 phosphorylation in response to
leptin. Very surprisingly, this provided evidence that when cAMP levels are increased,
leptin drives cells towards apoptosis associated with a marked decrease of Bcl2
protein levels and accompanied by down-regulation of
protein kinase A (PKA). The aim of the current study was to investigate the role of cAMP in
leptin-associated motility of
breast cancer cells. Here we show that cAMP elevation completely prevents
leptin-induced migration of MDA-MB-231
breast cancer cells. Interestingly, the inhibition by cAMP-elevating agents of
leptin-mediated cell migration is accompanied by a strong decrease of β3
integrin subunit and
focal adhesion kinase (FAK)
protein levels. Analysis of the underlying cAMP-dependent molecular mechanisms revealed that PKA blockers partly counteract the inhibition of
leptin-induced migration and completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue that specifically activates
Epac and not PKA has an inhibitory effect on
leptin-induced cell migration as well. The present study confirms initial evidence for the efficacy of cAMP elevation against oncogenic effects of
leptin, identifies β3
integrin subunit and FAK as
proteins strongly down-regulated by cAMP elevation, and suggests that both cAMP/PKA- and cAMP/
Epac-dependent pathways are involved in inhibition of
leptin-induced migration of MDA-MB-231
breast cancer cells. The potential clinical significance and therapeutic applications of our data are discussed.