JOURNAL BROWSE
Search
Advanced SearchSearch Tips
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
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
 Title & Authors
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
Montazeri, Hamed; Bouzari, Saeid; Azadmanesh, Kayhan; Ostad, Seyed Nasser; Ghahremani, Mohammad Hossein;
  PDF(new window)
 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 -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 g rowth properties of MCF-7 cells, enhancing the oncogenic activity of these ER positive breast cancer cells.
 Keywords
Cyclin E;breast cancer;low molecular weight isoforms;p53;estrogen receptor;
 Language
English
 Cited by
 References
1.
Ababneh M, Gotz C, Montenarh M (2001). Downregulation of the cdc2/cyclin B protein kinase activity by binding of p53 to p34(cdc2). Biochem Biophys Res Commun, 283, 507-12. crossref(new window)

2.
Akli S, Bui T, Wingate H, et al (2010). Low-molecular-weight cyclin E can bypass letrozole-induced G1 arrest in human breast cancer cells and tumors. Clin Cancer Res, 16, 1179-90. crossref(new window)

3.
Akli S, Van Pelt CS, Bui T, et al (2007). Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway. Cancer Res, 67, 7212-22. crossref(new window)

4.
Akli S, Zheng PJ, Multani AS, et al (2004). Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Res, 64, 3198-208. crossref(new window)

5.
Alsina M, Landolfi S, Aura C, et al (2015). Cyclin E amplification/overexpression is associated with poor prognosis in gastric cancer. Ann Oncol, 26, 438-9. crossref(new window)

6.
Angeloni SV, Martin MB, Garcia-Morales P, et al (2004). Regulation of estrogen receptor-alpha expression by the tumor suppressor gene p53 in MCF-7 cells. J Endocrinol, 180, 497-504. crossref(new window)

7.
Band V, De Caprio JA, Delmolino L, et al (1991). Loss of p53 protein in human papillomavirus type 16 E6-immortalized human mammary epithelial cells. J Virol, 65, 6671-6.

8.
Bedrosian I, Lu KH, Verschraegen C, et al (2004). Cyclin E deregulation alters the biologic properties of ovarian cancer cells. Oncogene, 23, 2648-57. crossref(new window)

9.
Bratton MR, Duong BN, Elliott S, et al (2010). Regulation of ERalpha-mediated transcription of Bcl-2 by PI3K-AKT crosstalk: implications for breast cancer cell survival. Int J Oncol, 37, 541-50.

10.
Caldon CE, Sergio CM, Kang J, et al (2012). Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther, 11, 1488-99. crossref(new window)

11.
Cayrol C, Knibiehler M, Ducommun B (1998). p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene, 16, 311-20. crossref(new window)

12.
Chung K, Hovanessian-Larsen LJ, Hawes D, et al (2012). Breast epithelial cell proliferation is markedly increased with short-term high levels of endogenous estrogen secondary to controlled ovarian hyperstimulation. Breast Cancer Res Treat, 132, 653-60. crossref(new window)

13.
Davidson B, Skrede M, Silins I, et al (2007). Low-molecular weight forms of cyclin E differentiate ovarian carcinoma from cells of mesothelial origin and are associated with poor survival in ovarian carcinoma. Cancer, 110, 1264-71. crossref(new window)

14.
Donnellan R, Chetty R (1999). Cyclin E in human cancers. FASEB J, 13, 773-80. crossref(new window)

15.
Dulic V, Drullinger LF, Lees E, et al (1993). Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci USA, 90, 11034-8. crossref(new window)

16.
Ekholm-Reed S, Spruck CH, Sangfelt O, et al (2004). Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer. Cancer Res, 64, 795-800. crossref(new window)

17.
Ekholm SV, Reed SI (2000). Regulation of G(1) cyclindependent kinases in the mammalian cell cycle. Curr Opin Cell Biol, 12, 676-84. crossref(new window)

18.
el-Deiry WS, Tokino T, Velculescu VE, et al (1993). WAF1, a potential mediator of p53 tumor suppression. Cell, 75, 817-25. crossref(new window)

19.
Gao S, Ma JJ, Lu C (2013). Prognostic value of cyclin E expression in breast cancer: a meta-analysis. Tumour Biol, 34, 3423-30. crossref(new window)

20.
Gladden AB, Diehl JA (2003). Cell cycle progression without cyclin E/CDK2: breaking down the walls of dogma. Cancer Cell, 4, 160-2. crossref(new window)

21.
Haldar S, Negrini M, Monne M, et al (1994). Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res, 54, 2095-7.

22.
Harwell RM, Porter DC, Danes C, et al (2000). Processing of cyclin E differs between normal and tumor breast cells. Cancer Res, 60, 481-9.

23.
Hermeking H, Lengauer C, Polyak K, et al (1997). 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell, 1, 3-11. crossref(new window)

24.
Hess KR, Pusztai L, Buzdar AU, et al (2003). Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat, 78, 105-18. crossref(new window)

25.
Hinds PW, Mittnacht S, Dulic V, et al (1992). Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell, 70, 993-1006. crossref(new window)

26.
Hou J, Wang X, Li Y, et al (2012). 17beta-estradiol induces both up-regulation and processing of cyclin E in a calpaindependent manner in MCF-7 breast cancer cells. FEBS Lett, 586, 892-6. crossref(new window)

27.
Hwang HC, Clurman BE (2005). Cyclin E in normal and neoplastic cell cycles. Oncogene, 24, 2776-86. crossref(new window)

28.
Jaafar H, Abdullah S, Murtey MD, et al (2012). Expression of Bax and Bcl-2 in tumour cells and blood vessels of breast cancer and their association with angiogenesis and hormonal receptors. Asian Pac J Cancer Prev, 13, 3857-62. crossref(new window)

29.
Jiang Z, Guo J, Shen J, et al (2012). The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells. J Exp Clin Cancer Res, 31, 42. crossref(new window)

30.
Kastan MB, Zhan Q, el-Deiry WS, et al (1992). A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell, 71, 587-97. crossref(new window)

31.
Keyomarsi K, Conte D, Jr, Toyofuku W, et al (1995). Deregulation of cyclin E in breast cancer. Oncogene, 11, 941-50.

32.
Keyomarsi K, Pardee AB (1993). Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci U S A, 90, 1112-6. crossref(new window)

33.
Keyomarsi K, Tucker SL, Buchholz TA, et al (2002). Cyclin E and survival in patients with breast cancer. N Engl J Med, 347, 1566-75. crossref(new window)

34.
Khan SA, Rogers MA, Khurana KK, et al (1998). Estrogen receptor expression in benign breast epithelium and breast cancer risk. J Natl Cancer Inst, 90, 37-42. crossref(new window)

35.
Khan SA, Sachdeva A, Naim S, et al (1999). The normal breast epithelium of women with breast cancer displays an aberrant response to estradiol. Cancer Epidemiol Biomarkers Prev, 8, 867-72.

36.
Khan SA, Yee KA, Kaplan C, et al (2002). Estrogen receptor alpha expression in normal human breast epithelium is consistent over time. Int J Cancer, 102, 334-7. crossref(new window)

37.
Knappskog S, Lonning PE (2012). P53 and its molecular basis to chemoresistance in breast cancer. Expert Opin Ther Targets, 16, 23-30. crossref(new window)

38.
Koff A, Cross F, Fisher A, et al (1991). Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell, 66, 1217-28. crossref(new window)

39.
Lauper N, Beck AR, Cariou S, et al (1998). Cyclin E2: a novel CDK2 partner in the late G1 and S phases of the mammalian cell cycle. Oncogene, 17, 2637-43. crossref(new window)

40.
le Sage C, Nagel R, Egan DA, et al (2007). Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J, 26, 3699-708. crossref(new window)

41.
Lindahl T, Landberg G, Ahlgren J, et al (2004). Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer. Carcinogenesis, 25, 375-80.

42.
Liu SZ, Zhang F, Chang YX, et al (2013). Prognostic impact of cyclin D1, cyclin E and P53 on gastroenteropancreatic neuroendocrine tumours. Asian Pac J Cancer Prev, 14, 419-22. crossref(new window)

43.
Liu W, Konduri SD, Bansal S, et al (2006). Estrogen receptoralpha binds p53 tumor suppressor protein directly and represses its function. J Biol Chem, 281, 9837-40. crossref(new window)

44.
Liu X, Sempere LF, Galimberti F, et al (2009). Uncovering growth-suppressive MicroRNAs in lung cancer. Clin Cancer Res, 15, 1177-83. crossref(new window)

45.
Macdonald JI, Dick FA (2012). Posttranslational modifications of the retinoblastoma tumor suppressor protein as determinants of function. Genes Cancer, 3, 619-33. crossref(new window)

46.
Minella AC, Swanger J, Bryant E, et al (2002). p53 and p21 form an inducible barrier that protects cells against cyclin E-cdk2 deregulation. Curr Biol, 12, 1817-27. crossref(new window)

47.
Miyashita T, Krajewski S, Krajewska M, et al (1994). Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene, 9, 1799-805.

48.
Miyashita T, Reed JC (1995). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell, 80, 293-9. crossref(new window)

49.
Niu D, Wang G, Wang X (2015). Up-regulation of cyclin E in breast cancer via estrogen receptor pathway. Int J Clin Exp Med, 8, 910-5.

50.
Ohtani K, DeGregori J, Nevins JR (1995). Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci U S A, 92, 12146-50. crossref(new window)

51.
Ohtsubo M, Theodoras AM, Schumacher J, et al (1995). Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol, 15, 2612-24. crossref(new window)

52.
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell, 74, 609-19. crossref(new window)

53.
Osborne CK (1998). Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat, 51, 227-38. crossref(new window)

54.
Panahi M, Saki N, Ashourzadeh S, et al (2013). Expressional correlation of human epidermal growth factor receptor 2, estrogen/progesterone receptor and protein 53 in breast cancer. Asian Pac J Cancer Prev, 14, 3699-703. crossref(new window)

55.
Porter DC, Zhang N, Danes C, et al (2001). Tumor-specific proteolytic processing of cyclin E generates hyperactive lower-molecular-weight forms. Mol Cell Biol, 21, 6254-69. crossref(new window)

56.
Potemski P, Kusinska R, Watala C, et al (2006a). Cyclin E expression in breast cancer correlates with negative steroid receptor status, HER2 expression, tumor grade and proliferation. J Exp Clin Cancer Res, 25, 59-64.

57.
Potemski P, Pluciennik E, Bednarek AK, et al (2006b). Cyclin E expression in operable breast cancer quantified using realtime RT-PCR: a comparative study with immunostaining. Jpn J Clin Oncol, 36, 142-9. crossref(new window)

58.
Raghav PK, Verma YK, Gangenahalli GU (2012). Peptide screening to knockdown Bcl-2's anti-apoptotic activity: implications in cancer treatment. Int J Biol Macromol, 50, 796-814. crossref(new window)

59.
Rengarajan T, Nandakumar N, Rajendran P, et al (2014). D-pinitol promotes apoptosis in MCF-7 cells via induction of p53 and Bax and inhibition of Bcl-2 and NF-kappaB. Asian Pac J Cancer Prev, 15, 1757-62. crossref(new window)

60.
Richardson H, O'Keefe LV, Marty T, et al (1995). Ectopic cyclin E expression induces premature entry into S phase and disrupts pattern formation in the Drosophila eye imaginal disc. Development, 121, 3371-9.

61.
Roemer K, Friedmann T (1993). Modulation of cell proliferation and gene expression by a p53-estrogen receptor hybrid protein. Proc Natl Acad Sci U S A, 90, 9252-6. crossref(new window)

62.
Sayeed A, Konduri SD, Liu W, et al (2007). Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res, 67, 7746-55. crossref(new window)

63.
Scuderi R, Palucka KA, Pokrovskaja K, et al (1996). Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage. Blood, 87, 3360-7.

64.
Shaye A, Sahin A, Hao Q, et al (2009). Cyclin E deregulation is an early event in the development of breast cancer. Breast Cancer Res Treat, 115, 651-9. crossref(new window)

65.
Smith FB, Puerto CD, Sagerman P (2001). Relationship of estrogen and progesterone receptor protein levels in carcinomatous and adjacent non-neoplastic epithelium of the breast: a histopathologic and image cytometric study. Breast Cancer Res Treat, 65, 241-7. crossref(new window)

66.
Spruck CH, Won KA, Reed SI (1999). Deregulated cyclin E induces chromosome instability. Nature, 401, 297-300. crossref(new window)

67.
Tu K, Zheng X, Zhou Z, et al (2013). Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E. PLoS One, 8, 68574. crossref(new window)

68.
Wang A, Yoshimi N, Suzui M, et al (1996). Different expression patterns of cyclins A, D1 and E in human colorectal cancer. J Cancer Res Clin Oncol, 122, 122-6. crossref(new window)

69.
Weinberg RA (1995). The retinoblastoma protein and cell cycle control. Cell, 81, 323-30. crossref(new window)

70.
Wingate H, Bedrosian I, Akli S, et al (2003). The low molecular weight (LMW) isoforms of cyclin E deregulate the cell cycle of mammary epithelial cells. Cell Cycle, 2, 461-6.

71.
Wingate H, Zhang N, McGarhen MJ, et al (2005). The tumorspecific hyperactive forms of cyclin E are resistant to inhibition by p21 and p27. J Biol Chem, 280, 15148-57. crossref(new window)

72.
Wu Y, Mehew JW, Heckman CA, et al (2001). Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene, 20, 240-51. crossref(new window)

73.
Xiong Y, Connolly T, Futcher B, et al (1991). Human D-type cyclin. Cell, 65, 691-9. crossref(new window)

74.
Yang Q, Sakurai T, Jing X, et al (1999). Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinoma. Pathol Int, 49, 775-80. crossref(new window)

75.
Yin XM, Oltvai ZN, Korsmeyer SJ (1994). BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature, 369, 321-3. crossref(new window)

76.
Zhang XH, Giuliano M, Trivedi MV, et al (2013). Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res, 19, 6389-97. crossref(new window)

77.
Zhao LW, Zhong XH, Yang SY, et al (2014). Inotodiol inhabits proliferation and induces apoptosis through modulating expression of cyclinE, p27, bcl-2, and bax in human cervical cancer HeLa cells. Asian Pac J Cancer Prev, 15, 3195-9. crossref(new window)