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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.

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Tumor-free survival in BALB/c mice bearing transplants of Trp53+/- mammary epithelium. Tumor incidence was also determined for outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. Donor mammary tissues from Trp53+/- mice (described in Figure 8a) were transplanted into epithelium-free mammary fat pads of 3-week-old wild-type mice. Beginning at 10 weeks of age, host mice received a 1.2-Gy dose of ionizing radiation once a week for 4 weeks to induce mammary tumors as described previously [30]. Mice were palpated weekly for mammary tumors until 65 weeks old. The incidence and latency of mammary tumors did not differ between epithelial outgrowths from the Trp53+/- mammary tissues from E+P-treated donors and iparous donors (P > 0.05). E+P, estradiol and progesterone; IR, ionizing radiation; Trp53, transformation-related protein 53 (gene in mouse encoding the p53 tumor suppressor protein); TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.
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Figure 9: Tumor-free survival in BALB/c mice bearing transplants of Trp53+/- mammary epithelium. Tumor incidence was also determined for outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. Donor mammary tissues from Trp53+/- mice (described in Figure 8a) were transplanted into epithelium-free mammary fat pads of 3-week-old wild-type mice. Beginning at 10 weeks of age, host mice received a 1.2-Gy dose of ionizing radiation once a week for 4 weeks to induce mammary tumors as described previously [30]. Mice were palpated weekly for mammary tumors until 65 weeks old. The incidence and latency of mammary tumors did not differ between epithelial outgrowths from the Trp53+/- mammary tissues from E+P-treated donors and iparous donors (P > 0.05). E+P, estradiol and progesterone; IR, ionizing radiation; Trp53, transformation-related protein 53 (gene in mouse encoding the p53 tumor suppressor protein); TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.

Mentions: Fragments (~1 mm3) of hormone-stimulated epithelium (E+P or parous) and iparous epithelium (placebo or AMV) were transplanted into contralateral mammary fat pads cleared of endogenous epithelium of the same host mouse as described previously [22]. The transplant epithelium was allowed to fill the fat pad. At 10 weeks of age, one group of mice bearing transplants was subjected to 5 Gy of γ-irradiation 6 hours prior to tissue harvest for TUNEL (terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling) assay (see timeline in Figure 8b). Another group was subjected to four weekly doses of 1.2 Gy of γ-irradiation [30] and used for the tumor study (see timeline in Figure 9). Animals in the tumor study were monitored by mammary gland palpation for up to 65 weeks. Tumors were removed when less than 1 cm in diameter to allow the continued monitoring of the contralateral gland. At the end of the tumor study, whole mounts were prepared for all remaining mammary glands to assess outgrowths. Transplant efficiency averaged 83%.


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)

Tumor-free survival in BALB/c mice bearing transplants of Trp53+/- mammary epithelium. Tumor incidence was also determined for outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. Donor mammary tissues from Trp53+/- mice (described in Figure 8a) were transplanted into epithelium-free mammary fat pads of 3-week-old wild-type mice. Beginning at 10 weeks of age, host mice received a 1.2-Gy dose of ionizing radiation once a week for 4 weeks to induce mammary tumors as described previously [30]. Mice were palpated weekly for mammary tumors until 65 weeks old. The incidence and latency of mammary tumors did not differ between epithelial outgrowths from the Trp53+/- mammary tissues from E+P-treated donors and iparous donors (P > 0.05). E+P, estradiol and progesterone; IR, ionizing radiation; Trp53, transformation-related protein 53 (gene in mouse encoding the p53 tumor suppressor protein); 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 9: Tumor-free survival in BALB/c mice bearing transplants of Trp53+/- mammary epithelium. Tumor incidence was also determined for outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. Donor mammary tissues from Trp53+/- mice (described in Figure 8a) were transplanted into epithelium-free mammary fat pads of 3-week-old wild-type mice. Beginning at 10 weeks of age, host mice received a 1.2-Gy dose of ionizing radiation once a week for 4 weeks to induce mammary tumors as described previously [30]. Mice were palpated weekly for mammary tumors until 65 weeks old. The incidence and latency of mammary tumors did not differ between epithelial outgrowths from the Trp53+/- mammary tissues from E+P-treated donors and iparous donors (P > 0.05). E+P, estradiol and progesterone; IR, ionizing radiation; Trp53, transformation-related protein 53 (gene in mouse encoding the p53 tumor suppressor protein); TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.
Mentions: Fragments (~1 mm3) of hormone-stimulated epithelium (E+P or parous) and iparous epithelium (placebo or AMV) were transplanted into contralateral mammary fat pads cleared of endogenous epithelium of the same host mouse as described previously [22]. The transplant epithelium was allowed to fill the fat pad. At 10 weeks of age, one group of mice bearing transplants was subjected to 5 Gy of γ-irradiation 6 hours prior to tissue harvest for TUNEL (terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling) assay (see timeline in Figure 8b). Another group was subjected to four weekly doses of 1.2 Gy of γ-irradiation [30] and used for the tumor study (see timeline in Figure 9). Animals in the tumor study were monitored by mammary gland palpation for up to 65 weeks. Tumors were removed when less than 1 cm in diameter to allow the continued monitoring of the contralateral gland. At the end of the tumor study, whole mounts were prepared for all remaining mammary glands to assess outgrowths. Transplant efficiency averaged 83%.

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