Dataset Information

Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.

ABSTRACT:

Background

Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between alpha6beta4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance.

Methods and findings

Using human breast cancer cell lines displaying different levels of alpha6beta4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the alpha6beta4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival.

Conclusions

We provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERbeta1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen.

SUBMITTER: Folgiero V

PROVIDER: S-EPMC2220038 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.

Folgiero Valentina V Avetrani Paolo P Bon Giulia G Di Carlo Selene E SE Fabi Alessandra A Nisticò Cecilia C Vici Patrizia P Melucci Elisa E Buglioni Simonetta S Perracchio Letizia L Sperduti Isabella I Rosanò Laura L Sacchi Ada A Mottolese Marcella M Falcioni Rita R

PloS one 20080213 2

<h4>Background</h4>Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear ...[more]

PMID: 18270579

Similar Datasets

Project description:The integrin alpha6beta4 has been implicated in two apparently contrasting processes, i.e., the formation of stable adhesions, and cell migration and invasion. To study the dynamic properties of alpha6beta4 in live cells two different beta4-chimeras were stably expressed in beta4-deficient PA-JEB keratinocytes. One chimera consisted of full-length beta4 fused to EGFP at its carboxy terminus (beta4-EGFP). In a second chimera the extracellular part of beta4 was replaced by EGFP (EGFP-beta4), thereby rendering it incapable of associating with alpha6 and thus of binding to laminin-5. Both chimeras induce the formation of hemidesmosome-like structures, which contain plectin and often also BP180 and BP230. During cell migration and division, the beta4-EGFP and EGFP-beta4 hemidesmosomes disappear, and a proportion of the beta4-EGFP, but not of the EGFP-beta4 molecules, become part of retraction fibers, which are occasionally ripped from the cell membrane, thereby leaving "footprints" of the migrating cell. PA-JEB cells expressing beta4-EGFP migrate considerably more slowly than those that express EGFP-beta4. Studies with a beta4-EGFP mutant that is unable to interact with plectin and thus with the cytoskeleton (beta4(R1281W)-EGFP) suggest that the stabilization of the interaction between alpha6beta4 and LN-5, rather than the increased adhesion to LN-5, is responsible for the inhibition of migration. Consistent with this, photobleaching and recovery experiments revealed that the interaction of beta4 with plectin renders the bond between alpha6beta4 and laminin-5 more stable, i.e., beta4-EGFP is less dynamic than beta4(R1281W)-EGFP. On the other hand, when alpha6beta4 is bound to laminin-5, the binding dynamics of beta4 to plectin are increased, i.e., beta4-EGFP is more dynamic than EGFP-beta4. We suggest that the stability of the interaction between alpha6beta4 and laminin-5 is influenced by the clustering of alpha6beta4 through the deposition of laminin-5 underneath the cells. This clustering ultimately determines whether alpha6beta4 will inhibit cell migration or not.

Project description:BackgroundERBB-2 is overexpressed in about 20% of breast cancers (BCs), indicating poor prognosis. The receptor activator of nuclear factor-κB (RANK) pathway is implicated in ERBB-2 (+) BC. The purpose of this study was to elucidate the underlying molecular mechanism of this interaction and the beneficial impact of dual targeting of RANK and ERBB-2 pathways.MethodsWe used SKBR3, MCF7, MDA-MB-453, and BT-474 human BC cell lines. We examined RANK and RANKL expression using RT-PCR, Western blot, and immunofluorescence. The evaluation of RANK expression in a cohort of BC patients was performed using immunohistochemistry. The interaction between RANK and ERBB family members was detected using proximity ligation assay (PLA), which enables the visualization of interacting proteins. We used inhibitors of both pathways [trastuzumab (T), pertuzumab (P), denosumab (D)]. NF-κB pathway activation was studied using Western blot. Cell growth and viability was evaluated using XTT, flow cytometry, and clonogenic assay. For cell migration evaluation, scratch assay was performed. Data were analyzed by one-way ANOVA.ResultsCell lines express RANK and RANKL. RANK immunostaining was also detected in human BC tissue samples. RANK receptor dimerizes with ERBB family members. RANK/ERBB-2 dimer number seems to be associated with ERBB-2 expression (SKBR3, 5.4; BT-474, 8.2; MCF7, 0.7; MDA-MB-453, 0.3). RANK/ERBB-2 dimers were decreased in the presence of the inhibitors D, T, and P, while they were increased after RANKL (R) treatment in SKBR3 (m, 5.4; D, 1.2; T, 1.9; DT, 0.6; TP, 1; DTP, 0.4; R, 11.8) and BT-474 (m, 8.2; D, 3.1; T, 4.3; DT, 0.7; TP, 3.4; DTP, 3.2; R, 11.6). Combination targeting of SKBR3 further decreased NF-κB pathway activation compared to single targeting. In SKBR3, RANKL and ERBB-2 blockage resulted in reduced cell proliferation, increased apoptosis, and lower metastatic potential compared to mock cells (m) and reversed values in RANKL presence. The combination treatment of SKBR3 with D, T, and P had an advantage in functional traits compared to single targeting. Denosumab suppressed NF-κB signaling and diminished proliferation rate in MDA-MB-453 cells. MCF7 did not correspond to inhibitors.ConclusionsThe results indicate a novel physical and molecular association between ERBB-2 and RANK pathways that affects ERBB-2 (+) BC growth. We also present data suggesting that the combination of anti-ERBB-2 agents and RANKL inhibitors have a potential direct anti-tumor effect and should be further tested in certain BC patients.

Dataset Information

Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.

Background

Methods and findings

Conclusions

Publications

Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets