Loss of beta4 integrin subunit reduces the tumorigenicity of MCF7 mammary cells and causes apoptosis upon hormone deprivation.
OBJECTIVE
The alpha6beta4 integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the beta4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ErbB-2-transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity. In this study, we investigated the biological consequences of interference with the endogenous beta4 integrin subunit expression.


METHODS
In vitro and in vivo tumor growth and the biochemical consequences of beta4 integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach.


RESULTS
Our data show that tumor growth of mammary tumor cells strictly depends on beta4 expression, confirming the relevance of beta4 protein in these cells. Moreover, interference with beta4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether beta4 expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous beta4 expression, upon hormone deprivation, induces caspase-9 and cytochrome c-mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 beta4-short hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment.


CONCLUSIONS
Overall, these results confirm the relevance of beta4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.
Bon
Giulia
G
Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy.
Folgiero
Valentina
V
Bossi
Gianluca
G
Felicioni
Laura
L
Marchetti
Antonio
A
Sacchi
Ada
A
Falcioni
Rita
R
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D039663:Integrin beta4 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D039663:Integrin beta4; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen; C546842:MTOR protein, human; C546843:mTOR protein, mouse