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

The protective effects of E+P treatment are not retained in epithelial transplant outgrowths. (a) Donor tissues were obtained from Trp53+/- mice that were treated as summarized in the diagram. One group of mice was implanted with pellets containing either no hormones or E+P. Another group of mice was allowed to undergo a full-term pregnancy or remained unmated to provide age-matched iparous tissue. (b) Radiation-induced apoptosis was determined in outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. The Trp53+/- mammary tissues from donors, described in panel (a), were transplanted into mammary fat pads of 3-week-old wild-type hosts and allowed to fill the glands. When 10 weeks old, the transplant-bearing hosts were irradiated 6 hours prior to tissue harvest. Radiation-induced apoptosis was low and did not differ among the mammary epithelial outgrowths from Trp53+/- placebo-treated, E+P-treated, age-matched virgin (AMV), or parous mammary tissues. E+P, estradiol and progesterone; 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
getmorefigures.php?uid=PMC2481490&req=5

Figure 8: The protective effects of E+P treatment are not retained in epithelial transplant outgrowths. (a) Donor tissues were obtained from Trp53+/- mice that were treated as summarized in the diagram. One group of mice was implanted with pellets containing either no hormones or E+P. Another group of mice was allowed to undergo a full-term pregnancy or remained unmated to provide age-matched iparous tissue. (b) Radiation-induced apoptosis was determined in outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. The Trp53+/- mammary tissues from donors, described in panel (a), were transplanted into mammary fat pads of 3-week-old wild-type hosts and allowed to fill the glands. When 10 weeks old, the transplant-bearing hosts were irradiated 6 hours prior to tissue harvest. Radiation-induced apoptosis was low and did not differ among the mammary epithelial outgrowths from Trp53+/- placebo-treated, E+P-treated, age-matched virgin (AMV), or parous mammary tissues. E+P, estradiol and progesterone; Trp53, transformation-related protein 53 (gene in mouse encoding the p53 tumor suppressor protein); TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.

Mentions: Donor mammary epithelium was obtained from the fourth mammary glands of 12- to 15-week-old BALB/c-Trp53+/- female mice that were treated as described above: they were treated neonatally with either E+P or placebo and were parous or AMVs. The timelines for treatment of donor mice are summarized in Figure 8a. The tissues were minced, then placed in cryovials containing 1 mL of DMEM/F-12 supplemented with 10% fetal bovine serum and 10% dimethylsulfoxide, and stored in liquid nitrogen until needed for transplantation.


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)

The protective effects of E+P treatment are not retained in epithelial transplant outgrowths. (a) Donor tissues were obtained from Trp53+/- mice that were treated as summarized in the diagram. One group of mice was implanted with pellets containing either no hormones or E+P. Another group of mice was allowed to undergo a full-term pregnancy or remained unmated to provide age-matched iparous tissue. (b) Radiation-induced apoptosis was determined in outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. The Trp53+/- mammary tissues from donors, described in panel (a), were transplanted into mammary fat pads of 3-week-old wild-type hosts and allowed to fill the glands. When 10 weeks old, the transplant-bearing hosts were irradiated 6 hours prior to tissue harvest. Radiation-induced apoptosis was low and did not differ among the mammary epithelial outgrowths from Trp53+/- placebo-treated, E+P-treated, age-matched virgin (AMV), or parous mammary tissues. E+P, estradiol and progesterone; 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 8: The protective effects of E+P treatment are not retained in epithelial transplant outgrowths. (a) Donor tissues were obtained from Trp53+/- mice that were treated as summarized in the diagram. One group of mice was implanted with pellets containing either no hormones or E+P. Another group of mice was allowed to undergo a full-term pregnancy or remained unmated to provide age-matched iparous tissue. (b) Radiation-induced apoptosis was determined in outgrowths of Trp53+/- mammary tissue transplanted into wild-type hosts. The timeline of treatments is summarized graphically in the upper panel. The Trp53+/- mammary tissues from donors, described in panel (a), were transplanted into mammary fat pads of 3-week-old wild-type hosts and allowed to fill the glands. When 10 weeks old, the transplant-bearing hosts were irradiated 6 hours prior to tissue harvest. Radiation-induced apoptosis was low and did not differ among the mammary epithelial outgrowths from Trp53+/- placebo-treated, E+P-treated, age-matched virgin (AMV), or parous mammary tissues. E+P, estradiol and progesterone; Trp53, transformation-related protein 53 (gene in mouse encoding the p53 tumor suppressor protein); TUNEL, terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling.
Mentions: Donor mammary epithelium was obtained from the fourth mammary glands of 12- to 15-week-old BALB/c-Trp53+/- female mice that were treated as described above: they were treated neonatally with either E+P or placebo and were parous or AMVs. The timelines for treatment of donor mice are summarized in Figure 8a. The tissues were minced, then placed in cryovials containing 1 mL of DMEM/F-12 supplemented with 10% fetal bovine serum and 10% dimethylsulfoxide, and stored in liquid nitrogen until needed for transplantation.

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