title: Overexpression of Cyclin E and its Low Molecular Weight Isoforms Cooperate with Loss of p53 in Promoting Oncogenic Properties of MCF-7 Breast Cancer Cells.
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.
authors.affiliation: Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran E-mail : mhghahremani@tums.ac.ir.
authors.forename: Hamed
authors.initials: H
authors.lastname: Montazeri
authors.forename: Saeid
authors.initials: S
authors.lastname: Bouzari
authors.forename: Kayhan
authors.initials: K
authors.lastname: Azadmanesh
authors.forename: Seyed Nasser
authors.initials: SN
authors.lastname: Ostad
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Ghahremani
mesh_terms: D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D061986:MCF-7 Cells; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019927:Cyclin E; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D004958:Estradiol