Divergent behavior of cyclin E and its low molecular weight isoforms to progesterone-induced growth inhibition in MCF-7 cells

Authors

1 Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran

2 Department of Virology, Pasteur Institute of Iran, Tehran, Iran

3 Department of Toxicology-Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Background: Progesterone is a steroid hormone that modulates proliferation and differentiation in a cell phase and tissue-specific manner. Its function in breast cancer cells is of great significance since it can predict susceptibility of tumor cells to inhibitory effects of progesterone as adjuvant therapy.
Materials and Methods: Stable clones overexpressing cyclin E (EL) and its low molecular weight isoforms (LMW-Es) were generated and treated with various concentrations of progesterone. Cell proliferation was assessed 24 and 48 h after the treatment. Changes in progesterone receptor (PR) expression were measured by real-time polymerase chain reaction.
Results: Here we demonstrated that overexpression of EL and LMW-Es have divergent effects with regard to progesterone response. We found that progesterone could significantly decrease the growth rate of EL-expressing cells in the second cell cycle after treatment; however, progesterone was ineffective to arrest growth of LMW-Es expressing cells. PR expression level was at control level in EL-expressing cells but was downregulatedin LMW-Esexpressing clones.
Conclusion: These results were in line with progesterone response of studied cells. The drop in PR expression together with altered distribution of p21 and p27 can explain different effects of cyclin E isoforms expression on progesterone responsivity. These data bring cyclin E status of cancer cells as a marker for predicting the efficacy of progesterone treatment.

Keywords

1.
Mote PA, Graham JD, Clarke CL. Progesterone receptor isoforms in normal and malignant breast. Ernst Schering Found Symp Proc 2007;77-107.  Back to cited text no. 1
    
2.
Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev. 1997;18:502-19.  Back to cited text no. 2
    
3.
Lonard DM, O'Malley B W. Nuclear receptor coregulators: Judges, juries, and executioners of cellular regulation. Mol Cell 2007;27:691-700.  Back to cited text no. 3
    
4.
Aupperlee MD, Haslam SZ. Differential hormonal regulation and function of progesterone receptor isoforms in normal adult mouse mammary gland. Endocrinology 2007;148:2290-300.  Back to cited text no. 4
    
5.
Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev 1990;11:266-301.  Back to cited text no. 5
    
6.
Musgrove EA, Lee CS, Sutherland RL. Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes. Mol Cell Biol 1991;11:5032-43.  Back to cited text no. 6
    
7.
Rose PG. Endometrial carcinoma. N Engl J Med 1996;335:640-9.  Back to cited text no. 7
    
8.
Santen RJ, Manni A, Harvey H, Redmond C. Endocrine treatment of breast cancer in women. Endocr Rev 1990;11:221-65.  Back to cited text no. 8
    
9.
Musgrove EA, Sutherland RL. Cell cycle control by steroid hormones. Semin Cancer Biol 1994;5:381-9.  Back to cited text no. 9
    
10.
Musgrove EA, Hamilton JA, Lee CS, Sweeney KJ, Watts CK, Sutherland RL. Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol Cell Biol 1993;13:3577-87.  Back to cited text no. 10
    
11.
Musgrove EA, Lee CS, Cornish AL, Swarbrick A, Sutherland RL. Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. Mol Endocrinol 1997;11:54-66.  Back to cited text no. 11
    
12.
Musgrove EA, Sarcevic B, Sutherland RL. Inducible expression of cyclin D1 in T-47D human breast cancer cells is sufficient for Cdk2 activation and pRB hyperphosphorylation. J Cell Biochem 1996;60:363-78.  Back to cited text no. 12
    
13.
Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 1997;272:10882-94.  Back to cited text no. 13
    
14.
Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL. Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 1995;9:1804-13.  Back to cited text no. 14
    
15.
Bortner DM, Rosenberg MP. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 1997;17:453-9.  Back to cited text no. 15
    
16.
Keyomarsi K, Herliczek TW. The role of cyclin E in cell proliferation, development and cancer. Prog Cell Cycle Res 1997;3:171-91.  Back to cited text no. 16
    
17.
Keyomarsi K, Conte D Jr., Toyofuku W, Fox MP. Deregulation of cyclin E in breast cancer. Oncogene 1995;11:941-50.  Back to cited text no. 17
    
18.
Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, et al. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 1992;257:1689-94.  Back to cited text no. 18
    
19.
Schraml P, Bucher C, Bissig H, Nocito A, Haas P, Wilber K, et al. Cyclin E overexpression and amplification in human tumours. J Pathol 2003;200:375-82.  Back to cited text no. 19
    
20.
Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 2001;294:173-7.  Back to cited text no. 20
    
21.
Lerner M, Lundgren J, Akhoondi S, Jahn A, Ng HF, Akbari Moqadam F, et al. MiRNA-27a controls FBW7/hCDC4-dependent cyclin E degradation and cell cycle progression. Cell Cycle 2011;10:2172-83.  Back to cited text no. 21
    
22.
Harwell RM, Porter DC, Danes C, Keyomarsi K. Processing of cyclin E differs between normal and tumor breast cells. Cancer Res 2000;60:481-9.  Back to cited text no. 22
    
23.
Porter DC, Zhang N, Danes C, McGahren MJ, Harwell RM, Faruki S, et al. Tumor-specific proteolytic processing of cyclin E generates hyperactive lower-molecular-weight forms. Mol Cell Biol 2001;21:6254-69.  Back to cited text no. 23
    
24.
Akli S, Zheng PJ, Multani AS, Wingate HF, Pathak S, Zhang N, et al. Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Res 2004;64:3198-208.  Back to cited text no. 24
    
25.
Wingate H, Puskas A, Duong M, Bui T, Richardson D, Liu Y, et al. Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression. Cell Cycle 2009;8:1062-8.  Back to cited text no. 25
    
26.
Akli S, Bui T, Wingate H, Biernacka A, Moulder S, Tucker SL, et al. Low-molecular-weight cyclin E can bypass letrozole-induced G1 arrest in human breast cancer cells and tumors. Clin Cancer Res 2010;16:1179-90.  Back to cited text no. 26
    
27.
Yang C, Chen L, Li C, Lynch MC, Brisken C, Schmidt EV. Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression. Mol Cell Biol 2010;30:3111-25.  Back to cited text no. 27
    
28.
Musgrove EA, Swarbrick A, Lee CS, Cornish AL, Sutherland RL. Mechanisms of cyclin-dependent kinase inactivation by progestins. Mol Cell Biol 1998;18:1812-25.  Back to cited text no. 28
    
29.
Groshong SD, Owen GI, Grimison B, Schauer IE, Todd MC, Langan TA, et al. Biphasic regulation of breast cancer cell growth by progesterone: Role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Mol Endocrinol 1997;11:1593-607.  Back to cited text no. 29
    
30.
Swarbrick A, Lee CS, Sutherland RL, Musgrove EA. Cooperation of p27(Kip1) and p18(INK4c) in progestin-mediated cell cycle arrest in T-47D breast cancer cells. Mol Cell Biol 2000;20:2581-91.  Back to cited text no. 30
    
31.
Montazeri H, Bouzari S, Azadmanesh K, Ostad SN, Ghahremani MH. P53 but not cyclin E acts in A negative regulatory loop to controlHER-2 expression in MCF-7 breast carcinoma cell line. Acta Med Iran 2013;51:513-9.  Back to cited text no. 31
    
32.
Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 2002;30:e36.  Back to cited text no. 32