Chromosome instability (CIN) instigates various malignant phenotypes, including deregulated proliferation, apoptosis and invasion to initiate and sustain carcinogenesis. A major source of CIN in cancer is centrosome amplification (CA), defined as the acquisition of abnormal number of centrosomes (3 or more) that may result in defective mitosis, chromosome missegregation and aneuploidy. CA is present in pre-malignant breast lesions and high percentages of CA correlate with metastasis to the lymph nodes. CA may facilitate breast tumorigenesis, albeit this hypothesis has to be tested. Our laboratory found that CA and binucleation, intermediates to tetraploidy, are more likely to occur in Her2+ER-PR- (Her2+) breast cancers, while triple-negative (TN or Her2-ER-PR-) display other forms of CIN, such as micronuclei, defined as missegregated whole or fragmented chromosomes. The Her2 and TN subtypes differ from good-prognosis breast cancers such as luminal in that they accumulate high frequencies of CIN. Even though all breast cancer patients respond similarly to radiation therapy, Her2+ and TN patients are more likely to recur. Our laboratory searches for sources of CA and CIN in breast tumors and found that CA and CIN are suppressed by silencing of Cdk4 and the E2F activators. We have shown that silencing of CDK4 radiosensitizes TN and Her2+ breast cancer cells by activating intrinsic apoptotic pathways. We propose that inhibiting the cell and centrosome machinery would represent future treatment modalities for breast cancer.

Citation Format: Harold I. Saavedra. The Cdk4/E2F pathway drives centrosome amplification and chromosome instability in breast cancer cells. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA17.