Down-Regulation of the Oncogene Cyclin D1 Increases Migratory Capacity in Breast Cancer and Is Linked to Unfavorable Prognostic Features

Abstract

The oncogene cyclin D1 is highly expressed in many breast cancers and, despite its proliferation-activating properties, it has been linked to a less malignant phenotype. To clarify this observation, we focused on two key components of malignant behavior, migration and proliferation, and observed that quiescent G(0)/G(1) cells display an increased migratory capacity compared to cycling cells. We also found that the down-regulation of cyclin D1 in actively cycling cells significantly increased migration while also decreasing proliferation. When analyzing a large set of premenopausal breast cancers, we observed an inverse proliferation-independent link between cyclin D1 and tumor size and recurrence, suggesting that this protein might abrogate infiltrative malignant behavior in vivo. Finally, gene expression analysis after cyclin D1 down-regulation by siRNA confirmed changes in processes associated with migration and enrichment of our gene set in a metastatic poor prognosis signature. This novel function of cyclin D1 illustrates the interplay between tumor proliferation and migration and may explain the attenuation of malignant behavior in breast cancers with high cyclin D1 levels.

Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study

“…Patients showing low expression of Ki67 had a longer TTR with the highest levels of cyclin D 1 expression, whereas patients exhibiting higher levels of Ki67 had the shortest TTR with the lowest levels of cyclin results in a prolonged TTR in ER-positive, postmenopausal breast cancer patients. Similar results were observed in our previous study of randomised material from premenopausal breast cancer patients [47]. The relationship between cyclin D 1 , proliferation and prognosis hence seems to be complex, and this could in part be explained by potential additional functions for cyclin D 1 unrelated to proliferation control, as well as co-amplification and co-deletion of specific genes on chromosome 11q13, the locus harbouring CCND1.…”

High proliferation is associated with inferior outcome in male breast cancer patients

“…An in vitro study demonstrated that a decreased expression of cyclin D1 was linked to an enhanced infiltrative potential in the tumor, explained by the finding that cells in the quiescent phase had a greater migratory capacity. 27 The authors of the latter study strengthened their finding by demonstrating that cyclin D1 expression was inversely associated with tumor size in a female breast cancer material. This observation could not be verified in our material.…”

Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBPδ Expression and Contributes to Transformation of Breast Tumor Cells

“…Cyclin D1 is overexpressed in different cancers, including breast, and many studies have associated cyclin D1 with malignant cell features and tumor progression (35) including cell motility (41). In some reports, cyclin D1 was associated with reduced cell migration and more favorable prognosis (39), which may depend on other cofactors such as splice variants and availability of p27 KIP1 (40). Thus, the precise role of cyclin D1 downregulation in inhibition of cell transformation by C/EBP␦ signaling remains to be determined.…”