Abstract
Cyclin E, a key coordinator of the G1 to S transition in the cell cycle, may be deregulated in several malignancies, including breast cancer. The most significant aberration in cyclin E is its elastase mediated proteolytic cleavage into tumor specific low molecular weight isoforms (LMW-Es). LMW-Es are biochemically hyperactive and biologically drive tumorigenesis in transgenic mouse models. Additionally, expression of LMW-Es has been correlated with poor survival in breast cancer cases. Here we determine whether expression of LMW-Es in a breast cancer cell line that is naturally devoid of these deregulated forms would alter their progression through each phase of the cell cycle. The results revealed that LMW-Es expression resulted in an increased doubling time, concomitant with a predominant increase in the population in the S phase of the cell cycle. Moreover, downregulation of p53 in LMW-Es cells resulted in additional shortening of the doubling time and enrichment of cells in the S and G2/M phases of the cell cycle. Furthermore, expression of LMW-Es sensitized cells to β-estradiol (E2) mediated growth and changed expression patterns of estrogen receptor and Bcl-2. Intriguingly, expression of LMW-Es could surpass anti-apoptotic effects raised by p53 upregulation. Taken together these studies suggest that overexpression of LMW-Es in collaboration with p53 loss results in altered growth properties of MCF-7 cells, enhancing the oncogenic activity of these ER positive breast cancer cells.
Highlights
Cell cycle progression is governed by cyclins and their kinase partners, the cyclin dependent kinases (CDKs)
Our results reveal that the expression of either EL or any of LMW-Es promotes accumulation of cells in S
These results refer to the function of cyclin E as stimulating cell cycle progression by releasing E2F from retinoblastoma protein (Rb); induction of transcription of genes required for G1 to S phase transition (Hinds et al, 1992; Macdonald and Dick, 2012)
Summary
Cell cycle progression is governed by cyclins and their kinase partners, the cyclin dependent kinases (CDKs). Knockdown of cyclin E during development does not have a detrimental effect on the developing embryo, downregulation of cyclin E in many types of cancer results in senescence of apoptosis of these cells (Gladden and Diehl, 2003). These results suggest that while the function of cyclin E is redundant in normal cells or tissues, that many cancer cells become oncogenically addicted to the deregulated expression of cyclin E (Gladden and Diehl, 2003)
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