Limits...
Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice.

Dunphy KA, Blackburn AC, Yan H, O'Connell LR, Jerry DJ - Breast Cancer Res. (2008)

Bottom Line: This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones.However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and iparous donors.Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Veterinary & Animal Sciences and Molecular & Cellular Biology Program, University of Massachusetts, 300 Massachusetts Avenue, Amherst, MA 01003, USA.

ABSTRACT

Introduction: Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome.

Methods: Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues.

Results: Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both iparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and iparous donors.

Conclusion: Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.

Show MeSH

Related in: MedlinePlus

Effects of hormonal treatments on apoptosis in BALB/c-Trp53+/- mammary glands. (a) Levels of TUNEL-positive mammary epithelium from iparous mice were decreased significantly with dosage of Trp53 (Trp53+/+ > Trp53+/- > Trp53-/-) in both iparous and hormone-stimulated groups. Data from control groups and hormone-treated groups of mice were pooled to provide sufficient numbers for all genotypes. The iparous group represents placebo-treated and age-matched virgins. The hormone-stimulated group represents mammary tissues from mice treated with E+P and parous mice as described in Figure 2a. Bars indicate statistical differences between means: *P < 0.05; **P < 0.01.(b) The incidence of mammary tumors was monitored in both iparous and multiparous BALB/c-Trp53+/- female mice. The latency of spontaneous mammary tumors was increased in parous compared with iparous mice (P < 0.001). TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2481490&req=5

Figure 6: Effects of hormonal treatments on apoptosis in BALB/c-Trp53+/- mammary glands. (a) Levels of TUNEL-positive mammary epithelium from iparous mice were decreased significantly with dosage of Trp53 (Trp53+/+ > Trp53+/- > Trp53-/-) in both iparous and hormone-stimulated groups. Data from control groups and hormone-treated groups of mice were pooled to provide sufficient numbers for all genotypes. The iparous group represents placebo-treated and age-matched virgins. The hormone-stimulated group represents mammary tissues from mice treated with E+P and parous mice as described in Figure 2a. Bars indicate statistical differences between means: *P < 0.05; **P < 0.01.(b) The incidence of mammary tumors was monitored in both iparous and multiparous BALB/c-Trp53+/- female mice. The latency of spontaneous mammary tumors was increased in parous compared with iparous mice (P < 0.001). TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.

Mentions: BALB/c-Trp53+/- mice develop spontaneous mammary tumors, providing a model for breast cancer in Li-Fraumeni syndrome [32]. Therefore, we compared the effects of Trp53 genotype and hormonal treatments on radiation-induced apoptosis in mammary tissues. As no differences in responses were detected within the iparous control groups (AMV, neonatal placebo, mature placebo) or within the hormone-stimulated groups (parous, neonatal E+P, mature E+P), the data for these groups were pooled (as described in Materials and methods). This was necessary due to the spontaneous nonmammary tumors that are common among the Trp53-deficient mice and limited survival. The overall effect of Trp53 genotype was significant in both the iparous control and hormone-stimulated groups (Kruskal-Wallis test, P = 0.04 and 0.002, respectively). In the iparous group, responses in the Trp53+/+ mice were significantly greater than either Trp53+/- or Trp53-/- (Figure 6a). Apoptotic responses were also decreased significantly with decreasing dosage of Trp53 in the hormone-stimulated mice (P < 0.05). Thus, Trp53+/- mammary tissue is haploinsufficient with respect to radiation-induced apoptosis, but p53 activity can be increased significantly in Trp53+/- mammary epithelium following hormonal stimulation.


Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice.

Dunphy KA, Blackburn AC, Yan H, O'Connell LR, Jerry DJ - Breast Cancer Res. (2008)

Effects of hormonal treatments on apoptosis in BALB/c-Trp53+/- mammary glands. (a) Levels of TUNEL-positive mammary epithelium from iparous mice were decreased significantly with dosage of Trp53 (Trp53+/+ > Trp53+/- > Trp53-/-) in both iparous and hormone-stimulated groups. Data from control groups and hormone-treated groups of mice were pooled to provide sufficient numbers for all genotypes. The iparous group represents placebo-treated and age-matched virgins. The hormone-stimulated group represents mammary tissues from mice treated with E+P and parous mice as described in Figure 2a. Bars indicate statistical differences between means: *P < 0.05; **P < 0.01.(b) The incidence of mammary tumors was monitored in both iparous and multiparous BALB/c-Trp53+/- female mice. The latency of spontaneous mammary tumors was increased in parous compared with iparous mice (P < 0.001). TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481490&req=5

Figure 6: Effects of hormonal treatments on apoptosis in BALB/c-Trp53+/- mammary glands. (a) Levels of TUNEL-positive mammary epithelium from iparous mice were decreased significantly with dosage of Trp53 (Trp53+/+ > Trp53+/- > Trp53-/-) in both iparous and hormone-stimulated groups. Data from control groups and hormone-treated groups of mice were pooled to provide sufficient numbers for all genotypes. The iparous group represents placebo-treated and age-matched virgins. The hormone-stimulated group represents mammary tissues from mice treated with E+P and parous mice as described in Figure 2a. Bars indicate statistical differences between means: *P < 0.05; **P < 0.01.(b) The incidence of mammary tumors was monitored in both iparous and multiparous BALB/c-Trp53+/- female mice. The latency of spontaneous mammary tumors was increased in parous compared with iparous mice (P < 0.001). TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.
Mentions: BALB/c-Trp53+/- mice develop spontaneous mammary tumors, providing a model for breast cancer in Li-Fraumeni syndrome [32]. Therefore, we compared the effects of Trp53 genotype and hormonal treatments on radiation-induced apoptosis in mammary tissues. As no differences in responses were detected within the iparous control groups (AMV, neonatal placebo, mature placebo) or within the hormone-stimulated groups (parous, neonatal E+P, mature E+P), the data for these groups were pooled (as described in Materials and methods). This was necessary due to the spontaneous nonmammary tumors that are common among the Trp53-deficient mice and limited survival. The overall effect of Trp53 genotype was significant in both the iparous control and hormone-stimulated groups (Kruskal-Wallis test, P = 0.04 and 0.002, respectively). In the iparous group, responses in the Trp53+/+ mice were significantly greater than either Trp53+/- or Trp53-/- (Figure 6a). Apoptotic responses were also decreased significantly with decreasing dosage of Trp53 in the hormone-stimulated mice (P < 0.05). Thus, Trp53+/- mammary tissue is haploinsufficient with respect to radiation-induced apoptosis, but p53 activity can be increased significantly in Trp53+/- mammary epithelium following hormonal stimulation.

Bottom Line: This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones.However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and iparous donors.Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Veterinary & Animal Sciences and Molecular & Cellular Biology Program, University of Massachusetts, 300 Massachusetts Avenue, Amherst, MA 01003, USA.

ABSTRACT

Introduction: Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome.

Methods: Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues.

Results: Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both iparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and iparous donors.

Conclusion: Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.

Show MeSH
Related in: MedlinePlus