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

Estrogen receptor-alpha expression in spontaneous mammary tumors in Trp53+/- mice. Spontaneous mammary tumors from iparous (i-iii) and parous (iv-vi) BALB/c-Trp53+/- mice were stained with anti-ERα antibodies. Representative sections are shown for mammary intra-epithelial neoplasias (MIN) and adenocarcinomas that differ in ERα status. The tissues from iparous mice include (i) ERα+ MIN, (ii) ERα- adenocarcinoma, and (iii) ERα+ adenocarcinoma. The tissues from parous mice include (iv) ERα- MIN, (v) ERα- adenocarcinoma, and (vi) ERα+ adenocarcinoma. Scale bar = 20 μm. ERα, estrogen receptor-alpha.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Estrogen receptor-alpha expression in spontaneous mammary tumors in Trp53+/- mice. Spontaneous mammary tumors from iparous (i-iii) and parous (iv-vi) BALB/c-Trp53+/- mice were stained with anti-ERα antibodies. Representative sections are shown for mammary intra-epithelial neoplasias (MIN) and adenocarcinomas that differ in ERα status. The tissues from iparous mice include (i) ERα+ MIN, (ii) ERα- adenocarcinoma, and (iii) ERα+ adenocarcinoma. The tissues from parous mice include (iv) ERα- MIN, (v) ERα- adenocarcinoma, and (vi) ERα+ adenocarcinoma. Scale bar = 20 μm. ERα, estrogen receptor-alpha.

Mentions: The histopathology and ERα status of the tumors were also examined to determine whether parity altered the subtypes of tumors in the BALB/c-Trp53+/- mice. Adenocarcinomas represented the dominant histopathological class of tumors in both iparous and parous mice (Table 1) (86.2% and 87.5%, respectively). Although mammary intra-epithelial neoplasias (MINs) are considered precursors of adenocarcinomas, these were a small proportion of tissues because only palpable lesions were collected. Carcinosarcomas and adenosquamous tumors were infrequent. Expression of ERα was detected in MIN and adenocarcinomas (Figure 7). Among adenocarcinomas, the proportion positive for ERα was increased from 12% among the iparous group to 33% among the parous group (Table 1) (P < 0.001). The increase in ERα+ tumors may reflect a difference in the cellular origins of the tumors between iparous and parous mice. However, this may be confounded with the fact that the mammary tumors in older mice are often collected at an earlier stage of tumor progression because of comorbidities (for example, lymphomas). The mammary tumors in BALB/c-Trp53+/- mice appear to progress from ERα+ lesions to ERα- tumors (D.J. Jerry, unpublished data). Thus, the difference in ERα expression may reflect an earlier stage of progression among mammary tumors from parous mice due to the longer latencies.


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)

Estrogen receptor-alpha expression in spontaneous mammary tumors in Trp53+/- mice. Spontaneous mammary tumors from iparous (i-iii) and parous (iv-vi) BALB/c-Trp53+/- mice were stained with anti-ERα antibodies. Representative sections are shown for mammary intra-epithelial neoplasias (MIN) and adenocarcinomas that differ in ERα status. The tissues from iparous mice include (i) ERα+ MIN, (ii) ERα- adenocarcinoma, and (iii) ERα+ adenocarcinoma. The tissues from parous mice include (iv) ERα- MIN, (v) ERα- adenocarcinoma, and (vi) ERα+ adenocarcinoma. Scale bar = 20 μm. ERα, estrogen receptor-alpha.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Estrogen receptor-alpha expression in spontaneous mammary tumors in Trp53+/- mice. Spontaneous mammary tumors from iparous (i-iii) and parous (iv-vi) BALB/c-Trp53+/- mice were stained with anti-ERα antibodies. Representative sections are shown for mammary intra-epithelial neoplasias (MIN) and adenocarcinomas that differ in ERα status. The tissues from iparous mice include (i) ERα+ MIN, (ii) ERα- adenocarcinoma, and (iii) ERα+ adenocarcinoma. The tissues from parous mice include (iv) ERα- MIN, (v) ERα- adenocarcinoma, and (vi) ERα+ adenocarcinoma. Scale bar = 20 μm. ERα, estrogen receptor-alpha.
Mentions: The histopathology and ERα status of the tumors were also examined to determine whether parity altered the subtypes of tumors in the BALB/c-Trp53+/- mice. Adenocarcinomas represented the dominant histopathological class of tumors in both iparous and parous mice (Table 1) (86.2% and 87.5%, respectively). Although mammary intra-epithelial neoplasias (MINs) are considered precursors of adenocarcinomas, these were a small proportion of tissues because only palpable lesions were collected. Carcinosarcomas and adenosquamous tumors were infrequent. Expression of ERα was detected in MIN and adenocarcinomas (Figure 7). Among adenocarcinomas, the proportion positive for ERα was increased from 12% among the iparous group to 33% among the parous group (Table 1) (P < 0.001). The increase in ERα+ tumors may reflect a difference in the cellular origins of the tumors between iparous and parous mice. However, this may be confounded with the fact that the mammary tumors in older mice are often collected at an earlier stage of tumor progression because of comorbidities (for example, lymphomas). The mammary tumors in BALB/c-Trp53+/- mice appear to progress from ERα+ lesions to ERα- tumors (D.J. Jerry, unpublished data). Thus, the difference in ERα expression may reflect an earlier stage of progression among mammary tumors from parous mice due to the longer latencies.

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