Abstract
Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.
Highlights
Inflammatory breast cancer (IBC) is the most aggressive subtype of breast cancer, accounting for 2–5% of breast cancers in the United States but causing an estimated 10% of total breast cancer mortality
In addition to the different distribution of subtypes in IBC, when we evaluated freedom-from-recurrence as a function of cyclin E phenotype, we found that cyclin E phenotype did not predict outcome in IBC, in contrast to the highly significant correlation between cytoplasmic cyclin E and poorer outcome in the non-IBC cohort
Previous work from our group has shown that cytoplasmic Low-molecular weight isoform of cyclin E (LMW-E) has novel kinase-dependent functions outside of the cell cycle that contribute to its oncogenicity, for example, as a regulator of EMT and cancer stem-cell phenotypes [11]
Summary
Inflammatory breast cancer (IBC) is the most aggressive subtype of breast cancer, accounting for 2–5% of breast cancers in the United States but causing an estimated 10% of total breast cancer mortality This mortality occurs despite the use of modern chemotherapy regimens given in the neoadjuvant setting including both anthracyclines and taxanes, followed by modified radical mastectomy and comprehensive post-mastectomy radiation [1,2,3]. Similar analyses of IBC samples by the World Consortium have confirmed the presence of all of these subtypes in IBC, albeit in a different distribution [6] These results have not uncovered a significant number of novel unique targets for evaluation in IBC
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