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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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Changes in mammary gland architecture induced by estrogen and progesterone. Tissues from mice that were iparous (a, d), E+P-treated (b, e), and parous (c, f) were examined using whole mounts (a-c) and 4-μm sections stained with hematoxylin and eosin (d-f). Magnifications, × 4 (a-c) and × 100 (d-f). E+P, estrogen and progesterone.
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Figure 1: Changes in mammary gland architecture induced by estrogen and progesterone. Tissues from mice that were iparous (a, d), E+P-treated (b, e), and parous (c, f) were examined using whole mounts (a-c) and 4-μm sections stained with hematoxylin and eosin (d-f). Magnifications, × 4 (a-c) and × 100 (d-f). E+P, estrogen and progesterone.

Mentions: Treatment with E+P for mature (6 to 8 weeks of age) or neonatal (10 to 24 days of age) mice resulted in lobular-alveolar development along the ductal tree and histological features that were indistinguishable from the glands from parous-involuted mice (Figures 1b and 1e versus 1c and 1f). However, the architecture of mammary glands from E+P-treated and parous mice differs from that of glands of 10-week-old iparous mice (Figures 1a and 1d). Therefore, treatment with E+P mimics the effects of parity on mammary gland architecture.


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)

Changes in mammary gland architecture induced by estrogen and progesterone. Tissues from mice that were iparous (a, d), E+P-treated (b, e), and parous (c, f) were examined using whole mounts (a-c) and 4-μm sections stained with hematoxylin and eosin (d-f). Magnifications, × 4 (a-c) and × 100 (d-f). E+P, estrogen and progesterone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Changes in mammary gland architecture induced by estrogen and progesterone. Tissues from mice that were iparous (a, d), E+P-treated (b, e), and parous (c, f) were examined using whole mounts (a-c) and 4-μm sections stained with hematoxylin and eosin (d-f). Magnifications, × 4 (a-c) and × 100 (d-f). E+P, estrogen and progesterone.
Mentions: Treatment with E+P for mature (6 to 8 weeks of age) or neonatal (10 to 24 days of age) mice resulted in lobular-alveolar development along the ductal tree and histological features that were indistinguishable from the glands from parous-involuted mice (Figures 1b and 1e versus 1c and 1f). However, the architecture of mammary glands from E+P-treated and parous mice differs from that of glands of 10-week-old iparous mice (Figures 1a and 1d). Therefore, treatment with E+P mimics the effects of parity on mammary gland architecture.

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