In addition to their role in cell migration and adhesion, integrins elicit a series of transduction events that regulate cell-cycle progression and apoptosis in a process known as "outside-in" signaling. A second mode of integrin regulation known as "inside-out" signaling, in which the activation of major cell transduction cascades can influence the activation status of some integrins, has also been described. Here, we have assessed the role of the extracellular signal-regulated kinase (ERK1)/ERK2, mitogen-activated protein kinase (MAPK), and phospoinositide 3-kinase (PI-3'K) signaling pathways in the expression and function of alpha(v)beta(3) integrin in breast cancer models. Pharmacological inhibition of MEK1 and MEK2 with U0126 drastically increased the levels of alpha(v)beta(3) in Heregulin (HRG)-overexpressing MDA-MB-231 cells (231/WT, 231/VEC) and derivatives transfected with the antisense orientation of the HRG-beta2 full length cDNA (231/ASPOOL, 231/AS31). Interestingly, this was related to a significant decrease of viability and of the S- and G2/M subcompartment of the cell cycle in MDA MB 231 cells in response to U0126. Furthermore, specific inhibition of the PI-3'K pathway with LY294002 also induced an increase of alpha(v)beta(3) levels but to a lesser extent. Moreover, pretreatment of MDA-MB-231 cells with U0126 antagonized the effects of small peptidomimetic alpha(v)beta(3) antagonists. Remarkably, inhibition of the PI-3'K/AKT pathway did not exert the same effects, thus suggesting that the "outside-in" as well as the "inside-out" alpha(v)beta(3)-mediated signaling goes primarily through the ERK1/ERK2 MAPK pathway in MDA MB 231 breast cancer cells. Collectively, these results strongly suggest the existence of a bidirectional molecular connection alpha(v)beta(3)-ERK1/ERK2 MAPK that would regulate breast cancer cells survival and proliferation.