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Cancer Research | Clinical Cancer Research |
Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
Molecular Cancer Research | Cell Growth & Differentiation |
Division of Oncology, Department of Medicine [V. L. S.], Department of Medicinal Chemistry [E. C. D.], Division of Hospital Dentistry, Department of Restorative Dentistry [B. S. J.], and Division of General Internal Medicine, University of Washington, Department of Medicine [M. B. P.], University of Washington, and Division of Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington 98195 [S. J. C.]
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Abstract |
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Introduction |
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The actions of retinoids are thought to be mediated through specific nuclear RARs3
and retinoid X receptors belonging to the steroid/thyroid superfamily of transcription factors (17)
. There are three RAR isoforms: RAR-; -ß; and -
. Several lines of evidence suggest that the loss of expression of RAR-ß plays an important role in breast carcinogenesis. Whereas normal HMECs express RAR-ß mRNA, a majority of breast cancer cell lines fail to express this gene (18, 19, 20, 21)
. Recently, it has been reported that there is a progressive decrease in RAR-ß mRNA levels during breast carcinogenesis (22
, 23)
and a loss of heterozygosity on chromosome 3p24, which encodes the RAR-ß gene. It has also been observed that there is a loss of RAR-ß mRNA expression in breast cancer specimens as well as the morphologically normal-appearing adjacent tissue, but not in distal normal breast tissue (23
, 24)
. These observations suggest that the loss of RAR function may be an important event in mammary carcinogenesis.
We reported previously that ATRA and RARs may act to regulate the G1-S-phase cell cycle transition in both normal and malignant mammary epithelial cells (20 , 21) . Regulation of G1-S-phase arrest in malignant cells by DNA-damaging agents such as radiation and chemotherapy has been well studied and is thought to involve the coordinated expression of specific cell cycle-regulatory proteins including p53. However, there is very little information on the regulation of the G1-S-phase cell cycle check point in normal cells by endogenous compounds such as retinoids. Understanding the molecular mechanism by which retinoids regulate proliferation will likely be important in the rational design of future retinoid-based chemoprevention trials (25) .
In this report, we investigate whether suppression of p53 protein expression in HMECs inhibits ATRA-mediated growth arrest. The E6 protein of the cancer-associated HPV-16 binds to p53 and targets it for degradation through the ubiquitin pathway (26 , 27) . Retroviral constructs containing HPV-16 E6 have been developed to investigate the role of p53 expression in regulating growth arrest mediated by DNA-damaging agents (28) . Using a similar approach, we expressed the HPV-16 E6 protein in HMECs and observed that unlike that with DNA-damaging agents, G1-S-phase arrest mediated by ATRA is independent of the level of p53 protein expression.
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Results |
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Retroviral-mediated Expression of HPV-16 E6 Suppresses p53 Expression in HMECs.
Western blots were performed on AG11132-E6 cells and AG11132-LXSN vector controls (passage 11 and 35) to determine the relative levels of p53 protein. Expression of endogenous p53 protein was observed in AG11132-LXSN vector controls but was not detectable by Western analysis in AG11132-E6-transduced cells (Fig. 3)
.
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Despite the difference in the doubling times of untreated passage 18 AG11132-E6 and AG11132-LXSN vector control cells, both cell populations exhibited proportionally similar growth inhibition when treated with ATRA (Fig. 4B
; Table 1
). Passage 30 AG11132-E6 cells also retained sensitivity to ATRA (Fig. 4C)
. These data demonstrate that ATRA inhibits the proliferation of HMECs in culture, and that inhibition of p53 protein expression does not block the sensitivity of HMEC strain AG11132 to ATRA-mediated G1-S-phase arrest.
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Expression of Cell Cycle Mediators in AG11132-E6 Cells Undergoing ATRA-mediated G1-S-Phase Arrest.
We performed Western analysis to further investigate whether the suppression of p53 protein expression in AG11132-E6 cells altered the expression of other cell cycle mediators in HMECs undergoing ATRA-mediated G1-S-phase arrest.
We investigated whether the suppression of p53 expression in AG11132-E6 cells (passage 11) resulted in a change in p21 protein expression in ATRA-treated and untreated cells. There is no induction of p21 protein expression when AG11132-LXSN vector controls and AG11132-E6 cells are treated with ATRA for 48 h (Fig. 3)
. However, there is a decrease in the absolute level of p21 expression in uninduced AG11132-E6 cells relative to controls (Fig. 3)
. These data suggest that the sensitivity of this strain of HMECs to ATRA-induced G1-S-phase arrest is not dependent on the absolute level of p21 protein expression, and that growth arrest mediated by ATRA does not involve the induction of p21.
We next investigated the expression of cyclin D1/cdk4 in AG11132-E6 cells (passage 11) and AG11132-LXSN vector controls undergoing ATRA-induced growth inhibition. Both AG11132-E6 cells and AG11132-LXSN vector controls exhibited a significant absolute decrease in cyclin D1 and cdk4 protein levels temporally associated with ATRA-mediated G1-S-phase arrest (Fig. 3)
. However, the relative level of cyclin D1 expression in AG11132-E6 cells was markedly reduced relative to that in AG11132-LXSN vector controls (Fig. 3)
. Whereas these results suggest that there is a temporal association between ATRA-mediated G1-S-phase arrest and decreased levels of cyclin D1/cdk4 protein, it does not appear that the absolute level of cyclin D1 expression is critical.
The tumor suppressor protein pRB seems to play a critical role in mediating cell cycle progression. We observe that ATRA-mediated G1-S-phase arrest of AG11132-LXSN vector controls and AG11132-E6 cells is temporally associated with a significant decrease in the level of hyperphosphorylated pRB concomitant with the induction of growth arrest (Fig. 3)
. These observations suggest that suppression of p53 does not alter the expression of pRB in HMECs, and that ATRA-induced G1-S-phase arrest in HMECs is associated with a decreased level of hyperphosphorylation, independent of the level of p53 expression.
AG11132-E6 cells have an extended life span in culture relative to vector controls. We also investigated the relative levels of these cell cycle mediators in AG11132-E6 cells at passage 35 as they neared senescence. There was a slight decrease in the levels of p21 and pRB protein expression in AG11132-E6 cells at passage 35 relative to passage 11; however, the overall pattern of expression of these cell cycle mediators as a function of ATRA treatment was unchanged as they approached senescence (Fig. 3)
.
Proteasome Inhibitors Block ATRA-mediated G1-S-Phase Arrest of HMECs and Associated Decrease in Cyclin D1 Protein Levels.
We next investigated whether blocking the function of the 26S proteasome antagonizes ATRA-mediated growth arrest of HMECs and the associated decline in cyclin D protein levels. AG11132-E6 and AG11132-LXSN vector controls were treated with calpain inhibitor I (1.0 µM) for 1.5 h before treatment with 1.0 µM ATRA. We observed that calpain inhibitor I blocked the ability of ATRA to induce growth arrest (Fig. 6A)
and also inhibited the expected decline in cyclin D1 levels (Fig. 7)
. This finding was confirmed and extended by treating our target cells with a second proteasome inhibitor, lactacystin (2.0 µM), which also prevented the ability of ATRA to induce growth arrest (Fig. 6B)
and a decline in cyclin D1 levels (Fig. 7)
. These data are consistent with the view that ATRA treatment decreases the level of cyclin D1 expression by promoting proteolysis via a ubiquitin-dependent pathway.
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Discussion |
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Current molecular models of G1-S-phase arrest in mammalian cells have been primarily based on observations made in cells treated with DNA-damaging agents such as chemotherapeutic agents and ionizing radiation. In these model systems, G1-S-phase arrest was associated with the coordinated induction of p53 and p21 that subsequently regulated the activity of cyclin/cdk complexes and resulted in pRB hypophosphorylation (32, 33, 34, 35, 36, 37, 38, 39) . Suppression of p53 protein expression in human keratinocytes by HPV-16 E6 correlated with an inability of these cells to undergo growth arrest mediated by DNA-damaging agents (37) . Whereas p53 may play a pivotal role in regulating the growth-suppressive actions of DNA-damaging agents in malignant cells, it is unclear what role it may play in growth regulation mediated by endogenous hormones, vitamins, and cytokines in normal cells. It has recently, been reported that certain physiological signals that inhibit cell growth such as transforming growth factor ß or prostaglandin A2 may regulate pRB phosphorylation independent of p53 expression (40 , 41) . We hypothesized that ATRA may similarly regulate cell growth via a p53-independent pathway.
As observed previously, there is no temporal correlation between the initiation of ATRA-mediated G1-S-phase arrest in normal cells and the induction of p53 protein (Figs. 1
and 2
; Ref. 21
). G1-S-phase arrest mediated by ATRA starts at 24 h (Fig. 1)
, and there is no induction of p53 protein until 72 h after treatment (Fig. 2)
, when a majority of cells have undergone growth arrest (Fig. 1)
. Based on these observations, we hypothesized that p53 protein induction did not play a primary role in regulating ATRA-mediated G1-S-phase arrest, but we could not exclude the possibility that p53 expression played a permissive role.
To test whether p53 expression is critical for ATRA-mediated G1-S-phase arrest in normal cells, we suppressed p53 protein expression in HMECs using retroviral-mediated expression of the HPV-16 E6 protein. Expression of the HPV-16 E6 protein in HMEC strain AG11132 markedly reduced the level of intracellular p53 (Fig. 3)
. No correlation was found between the level of p53 expression and the ability of ATRA to induce growth inhibition (Fig. 4
; Table 1
) and G1-S-phase arrest (Table 2
; Fig. 5
).
Similar to retinoids, estrogens and antiestrogens have been observed to regulate proliferation via a pRB-dependent pathway (30
, 31
, 42)
. We tested the sensitivity of HMEC strain AG11132 to the proliferative effects of E2 and the growth-inhibitory effects of the antiestrogens TAM and OHT and observed that there was no decreased sensitivity to the effects of estrogens or antiestrogens in cells with decreased p53 levels (Fig. 8)
. These observations suggest that unlike DNA-damaging agents, growth regulation by endogenous compounds such as ATRA and estrogens does not depend on the level of p53 protein expression.
Biochemical analysis of untreated AG11132-E6 cells showed a significant decrease in the absolute levels of p21 and cyclin D1 relative to AG11132-LXSN vector controls (Fig. 1)
. The observed decrease in p21 protein levels in AG11132-E6 cells is an expected finding, because the p53 protein positively regulates the transcription of p21 (29)
. The mechanism by which a decrease in intracellular p53 protein levels results in a decrease in the level of cyclin D1 protein is less clear. AG11132-LXSN and AG11132-E6 cells demonstrate equal sensitivity to the growth-inhibitory effects of ATRA, suggesting that G1-S-phase arrest mediated by ATRA is independent of the absolute levels of p21 and cyclin D1 expression. However, cyclin D1 levels decline in both ATRA-treated AG11132-E6 and AG11132-LXSN cells (relative to untreated cells), suggesting that a decline in cyclin D1 expression may play a role in ATRA-mediated growth inhibition.
Overexpression and amplification of cyclin D1 have been observed in primary breast cancers, even at early stages of the disease (43 , 44) , and it is hypothesized that lack of coordinated expression of cyclin D1 might promote breast carcinogenesis. Dysregulated expression of cyclin D1 in the human breast cancer cell line T-47D induces progression from G1 to S phase (45) , and overexpression of cyclin D1 in breast cancer cells decreases the rate at which cells exit the cell cycle, allowing growth factor-independent cell cycle progression and pRB hyperphosphorylation (46) . These observations predict that dysregulated expression of exogenous cyclin D1 would result in retinoid resistance. However, ectopic expression of cyclin D1 in BEAS-2G immortalized bronchial epithelial cells did not alter the sensitivity of transductants to retinoid-mediated growth arrest (47) . Regulation of cyclin D1 protein levels by retinoids seems to involve posttranslational proteolysis. We observe that proteosome inhibitors calpain inhibitor I and lactacystin both inhibit the ability of ATRA to mediate G1-S-phase arrest and prevent the expected associated decline in cyclin D1 protein levels. These observations are similar to the reported response of BEAS-2G cells to calpain I inhibitor and lactacystin (47) .
p53-mediated G1-S-phase arrest requires the coordinated expression of a complex set of cell cycle-regulatory genes. At the present time, the precise molecular pathway by which ATRA mediates G1-S-phase arrest in is unknown. We observe that ATRA-mediated growth arrest in HMECs does not depend on the level of p53 protein expression. It is unclear, however, whether growth arrest mediated by ATRA uses the same downstream effectors as p53 or unique downstream effectors, or whether there is an overlap between the two pathways. The data presented here suggest that there may be some overlap between the two pathways, because there is a decrease in the levels of cyclin D1, cdk4, and hyperphosphorylated pRB temporally associated with ATRA-mediated G1-S-phase arrest, similar to p53-dependent growth arrest. There also seems to be cross-talk between the downstream effector targets of p53 and ATRA because (a) inhibition of p53 protein expression results in a decrease in the absolute levels of cyclin D1; and (b) ATRA regulates the expression of cyclin D1, cdk4, and hyperphosphorylated pRB. Additional experiments will be necessary to define the potential interaction between downstream mediators of p53- and ATRA-mediated G1-S-phase arrest.
The sensitivity of AG11132-E6 cells to ATRA-mediated growth inhibition despite the suppression of p53 expression suggests that retinoids might have chemotherapeutic potential for suppressing the growth of tumors lacking p53 function. These results suggest novel potential clinical applications for retinoids in the treatment of tumors that contain p53 mutations. It is interesting that a naturally occurring dietary compound is able to induce growth regulation independent of p53 expression, highlighting the importance of investigating physiological signal agents as potential chemoprevention and therapeutic agents.
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Materials and Methods |
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Cell Culture and Media.
Normal HMEC strain AG11132 (M. Stampfer 172R/AA7) was purchased from the National Institute of Aging, Cell Culture Repository (Coriell Institute; Ref. 48
). HMEC strain AG11132 was derived from normal mammary tissue obtained at reduction mammoplasty, has a limited life span in culture, and fails to divide after approximately 25 passages. AG11132 was at passage 8 at the time of receipt. Cells were grown in Mammary Epithelial Cell Basal Medium (Clonetics, San Diego, CA) supplemented with bovine pituitary extract (Clonetics CC4009; 4 µl/ml), insulin (Lake Placid, NY; 5 µg/ml), epidermal growth factor (Upstate Biotechnology, Inc.; 10 ng/ml), hydrocortisone (Sigma; 0.5 µg/ml), isoproterenol (Sigma; 10-5 M), and HEPES buffer (Sigma; 10 mM). G418 (Life Technologies, Inc., Grand Island, NY)-containing media was prepared by the addition of 300 µg/ml G418 to the standard media described above. Cells were cultured at 37°C in a humidified incubator with 5% CO2/95% air. We did not process our growth media to remove endogenous retinoids. Mycoplasma testing was performed as reported previously by Russell et al. (49)
.
Retroviral Transduction.
The LXSN16E6 retroviral vector containing the HPV-16 E6 coding sequence (provided by D. Galloway, Fred Hutchinson Cancer Research Center, Seattle, WA) has been described previously (29)
. AG11132 normal HMECs (passage 9) were plated in four T-75 tissue culture flasks (Corning) in standard medium and grown to 50% confluence. Transducing virions from either the PA317-LXSN16E6 or control PA317-LXSN (without insert) retroviral producer line were added at a multiplicity of infection at 1:1 in the presence of 4 µg/ml Polybrene (Sigma) to log-phase cells grown in T-75 flasks. The two remaining T-75 flasks were not infected with virus. After 48 h, the two flasks containing transduced cells and one flask with untransduced cells were selected with standard medium containing G418 (300 µg/ml). Cells were continued in G418-containing medium for 2 weeks until 100% of control untransduced cells were dead. The fourth flask of unselected, untransduced parental control cells was passaged in parallel with the selected, transduced experimental and vector control cells.
ATRA Cell Growth Curves.
AG11132-LXSN vector controls (passage 10 and 18) and AG11132-E6 transduced cells (passages 10, 18, and 30) were plated in duplicate at 1 x 104 cells/well in 12-well tissue culture plates (Corning) on day -1 and allowed to adhere. On day 0, the medium was replaced with standard medium with or without 1.0 µM ATRA. Untreated controls received an equivalent volume of ethanol solvent (0.1% final concentration). Cells were trypsinized at 24-h intervals and counted in triplicate.
Estrogen Proliferation Assays.
AG11132-LXSN vector controls (passage 10 or 11) and AG11132-E6 transduced cells (passages 10 or 11) were plated on day -4. On day -3, media were changed to Phenol Red-free Mammary Epithelial Cell Basal Medium (Clonetics) with standard media additives for 48 h. Cells were plated on day -1 in duplicate at 1 x 104 cells/well in 12-well tissue culture plates (Corning) and allowed to adhere. On day 0, the media was changed to either Phenol Red-free Mammary Epithelial Cell Basal Media or standard media with or without 5 nM E2. Cells were trypsinized at 24-h intervals and counted in triplicate.
Antiestrogen Cell Growth Curves.
AG11132-LXSN vector controls (passage 10) and AG11132-E6 transduced cells (passage 10) were plated in duplicate at 1 x 104 cells/well in 12-well tissue culture plates (Corning) on day -1 and allowed to adhere. On day 0, the medium was replaced with standard medium with or without 1.0 µM TAM or 100 nM OHT. Untreated controls received an equivalent volume of ethanol solvent (0.1% final concentration). Cells were trypsinized at 24-h intervals and counted in triplicate.
Proteasome Inhibitor Growth Curves.
AG11132-LXSN vector controls (passage 10) and AG11132-E6 transduced cells (passage 10) were plated in duplicate at 1 x 104 cells/well in 12-well tissue culture plates (Corning) on day -1 and allowed to adhere. On day 0, the medium was replaced with standard medium with or without 1.0 µM calpain inhibitor I or 2.0 µM lactacystin. After 1.5 h, cells were treated with or without 1.0 µM ATRA. Cells were trypsinized at 24-h intervals and counted in triplicate.
DNA Staining of Cell Nuclei with Propidium Iodide and FACS Analysis.
A total of 5 x 105 AG11132-P (passage 10), AG11132-LXSN (passage 1012), or AG11132-E6 cells (passage 1012) were plated in T-75 flasks (Corning) on day -1 and allowed to adhere. On day 0, the medium was removed and replaced with 20 ml of fresh medium. ATRA was added to the culture medium for a final concentration of 1.0 µM on days 0, 1, 2, and 3 for the preparation of day 4, 3, 2, and 1 time points, respectively. Cells were harvested on day 4 and did not exceed 70% confluence. Cells were trypsinized, and nuclei were isolated and stained with propidium iodide as reported previously (20)
. Nuclei were then analyzed by FACScan (20)
. Ten thousand events were collected in list mode fashion, stored, and analyzed on Muticycle AV software (Phoenix Flow Systems, San Diego, CA). Cells were treated similarly with either 100 nM OHT or 1.0 µM TAM, and nuclei were isolated and analyzed by FACScan.
Western Blotting.
Preparation of cellular lysates and immunoblotting were as described previously (21)
. Equal amounts of protein lysates (approximately 100 µg of total protein) were loaded on 10% polyacrylamide gels, and the gels were run and then electroblotted (Hoeffer) at 80 mA for 45 min onto Hybond enhanced chemiluminescence membrane (Amersham). The membrane was blocked with 20% BSA (Sigma) in PBS overnight at RT and then incubated with either a 1:100 dilution of mouse antihuman p53 (Oncogene Science Ab-2), a 1:100 dilution of mouse antihuman pRB antibody (PharMingen), a 1:100 dilution of mouse antihuman p21/WAF1 antibody (Santa Cruz Biotechnology), a 1:200 dilution of polyclonal rabbit antiserum against human cyclin D1 (Santa Cruz Biotechnology), or a 1:100 dilution of polyclonal mouse antiserum to human cdk4 (Santa Cruz Biotechnology) for 1 h at RT with agitation. The membrane was washed three to five times at RT with 250 ml of PBS containing 0.1% Tween and then incubated with either a horseradish peroxidase-conjugated goat antimouse IgG (Jackson ImmunoResearch) at a 1:35,000 dilution or a 1:2,000 dilution of horseradish peroxidase-conjugated protein A (Sigma) for 1 h at RT. The blot was washed again, and complexes were detected by using enhanced chemiluminescence Western blotting detection reagents (Amersham) as described by the manufacturer.
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Acknowledgments |
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Footnotes |
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1 Supported by a Pilot and Feasibility Award from the Clinical Research Unit, University of Washington (Seattle, WA), NIH National Institutes of Diabetes, Digestive and Kidney Disease, and 2P30 DK 35816-11 [to V. L. S.]. V. L. S. was supported by NIH K08 Clinical Investigator Award CA 68210-01, a New Investigator Award from the Clinical Nutrition Research Unit NIH National Institutes of Diabetes, Digestive and Kidney Disease, 2P30DK 35816-11, and a Susan G. Komen Breast Cancer Fellowship.
2 To whom requests for reprints should be addressed, at Arthur James Cancer Center, Ohio State University, A437A Starling Loving Hall, Columbus, OH 43210. Phone (614) 293-4766; Fax: (614) 293-7525; E-mail: seewaldt-1{at}medctr.osu.edu
3 The abbreviations used are: RAR, retinoic acid receptor; RXR, retinoid X receptor; RA, retinoic acid; ATRA, all-trans-retinoic acid; HMEC, human mammary epithelial cell; HPV-16, human papillomavirus type 16; RARE, RA response element; OHT, 4-OH-tamoxifen, TAM, tamoxifen, E2, 17-ß-estradiol, ECL, enhanced chemiluminescence; FACS, fluorescence-activated cell sorting; RT, room temperature; cdk, cyclin-dependent kinase.
Received for publication 3/24/98. Revision received 11/10/98. Accepted for publication 11/12/98.
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HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cancer Research | Clinical Cancer Research |
Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
Molecular Cancer Research | Cell Growth & Differentiation |