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Updated: Aug 8, 2026
Quantification of Breast Cancer Cell Invasiveness Using a Three-dimensional (3D) Model
Published on: June 11, 2014
A bidirectional "alpha(v)beta(3) integrin-ERK1/ERK2 MAPK" connection regulates the proliferation of breast cancer
Luciano Vellon1, Javier A Menendez, Ruth Lupu
1Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA.
Abstract:
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.
Insights
This study reveals that inhibiting the ERK1/ERK2 MAPK pathway significantly increases alpha(v)beta(3) integrin levels in breast cancer cells, impacting their viability and cell cycle progression. This highlights a critical bidirectional connection between alpha(v)beta(3) integrin and ERK1/ERK2 MAPK signaling in regulating cancer cell survival and proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Integrins mediate outside-in and inside-out signaling, influencing cell migration, adhesion, cell-cycle progression, and apoptosis.
- The roles of extracellular signal-regulated kinase (ERK1)/ERK2, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI-3'K) signaling pathways in alpha(v)beta(3) integrin expression and function within breast cancer models require further elucidation.
Purpose of the Study:
- To investigate the involvement of ERK1/ERK2 MAPK and PI-3'K signaling pathways in the regulation of alpha(v)beta(3) integrin expression and function in breast cancer.
- To determine the impact of inhibiting these pathways on breast cancer cell viability and cell-cycle progression.
Main Methods:
- Utilized pharmacological inhibitors U0126 (for MEK1/MEK2) and LY294002 (for PI-3'K) in Heregulin (HRG)-overexpressing MDA-MB-231 breast cancer cells and their derivatives.
- Assessed changes in alpha(v)beta(3) integrin levels, cell viability, and cell-cycle distribution (S and G2/M phases) following pathway inhibition.
- Evaluated the effect of U0126 pretreatment on the efficacy of alpha(v)beta(3) antagonists.
Main Results:
- Pharmacological inhibition of MEK1/MEK2 with U0126 drastically increased alpha(v)beta(3) integrin levels in MDA-MB-231 cells, accompanied by decreased cell viability and altered cell-cycle distribution.
- Inhibition of the PI-3'K pathway with LY294002 also increased alpha(v)beta(3) levels, but to a lesser extent.
- U0126 pretreatment antagonized the effects of alpha(v)beta(3) antagonists, and PI-3'K/AKT pathway inhibition did not yield similar effects, suggesting ERK1/ERK2 MAPK is the primary pathway involved.
Conclusions:
- A bidirectional molecular connection exists between alpha(v)beta(3) integrin and the ERK1/ERK2 MAPK pathway in MDA-MB-231 breast cancer cells.
- This connection plays a crucial role in regulating breast cancer cell survival and proliferation.
- Targeting the ERK1/ERK2 MAPK pathway represents a potential therapeutic strategy in breast cancer treatment.
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