Four human breast cancer cell lines with biallelic inactivating alpha-catenin gene mutations.
Mutations of E-cadherin have been identified in half of lobular breast cancers and diffuse-type gastric cancers, two tumor subtypes with remarkably similar pathological appearances including small rounded cells with scant cytoplasm and a diffuse growth pattern. A causal role for E-cadherin gene mutations in the lobular breast cancer phenotype was recently demonstrated in E-cadherin knock-out mice. These observations suggested that another gene in the E-cadherin tumor suppressor pathway might be mutated in lobular breast cancers with wild-type E-cadherin genes. Here, we identified E-cadherin gene mutations exclusively in human breast cancer cell lines that grow with a rounded cell morphology. Using expression analyses and gene mutation analyses, we have identified four biallelic inactivating alpha-catenin mutations among 55 human breast cancer cell lines. All four alpha-catenin mutations predicted premature termination of the encoded proteins, and concordantly, none of the four mutant cell lines expressed alpha-catenin proteins. Importantly, three of the alpha-catenin mutant cell lines had the rounded cell morphology and all 14 cell lines with the rounded cell morphology had mutations of either E-cadherin or alpha-catenin. As anticipated, loss of alpha-catenin protein expression was associated with the lobular subtype in primary breast cancers. Together, our observations suggest that alpha-catenin may be a new tumor suppressor gene that operates in the E-cadherin tumor suppressor pathway.
Hollestelle
Antoinette
A
Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. a.hollestelle@erasmusmc.nl
Elstrodt
Fons
F
Timmermans
Mieke
M
Sieuwerts
Anieta M
AM
Klijn
Jan G M
JG
Foekens
John A
JA
den Bakker
Michael A
MA
Schutte
Mieke
M
D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor / Q000378:metabolism; D048430:Cell Shape / Q000235:genetics; D018389:Codon, Nonsense; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D051178:alpha Catenin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
D015820:Cadherins; D018389:Codon, Nonsense; D009363:Neoplasm Proteins; D051178:alpha Catenin