Cyclin D1 protein expression and function in human breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Cyclin D1 is a cell-cycle regulator and proto-oncogene implicated in various human tumors, including breast cancer.
• Genetic evidence suggests cyclin D1's role, but protein abundance and properties in breast cancer remain understudied.

Purpose of the Study:

• To investigate the abundance and aberrant expression of cyclin D1 protein in primary breast carcinomas.
• To determine the significance of cyclin D1 protein abnormalities in breast cancer progression and its relationship with the retinoblastoma (Rb) protein pathway.

Main Methods:

• Monoclonal antibody immunohistochemistry was used to analyze cyclin D1 protein expression in 170 primary breast carcinoma specimens.
• Expression patterns were compared in matched lesions at different stages of tumor progression.
• Cell-cycle analysis and knockout experiments (antibody-mediated and anti-sense oligonucleotides) were performed on breast cancer cell lines.

Main Results:

• Aberrant nuclear overexpression/accumulation of cyclin D1 protein was observed in approximately 50% of breast carcinoma specimens.
• Cyclin D1 protein aberration appears to be an early event, maintained throughout tumor progression, including metastasis.
• Low cyclin D1 protein and mRNA levels were found in cell lines with mutant or SV40 T antigen-complexed Rb protein.
• Cell-cycle regulatory function of cyclin D1 is required in Rb-proficient breast cancer lines but not in Rb-deficient lines.

Conclusions:

• The frequency of cyclin D1 abnormalities in breast cancer may be higher than previously estimated from DNA amplification studies.
• The "Rb-cyclin D1 pathway" is a frequent target of oncogenic abnormalities in breast cancer.
• Cyclin D1's role in cell-cycle regulation is critical in Rb-proficient breast cancer cells.