Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 3/2008

Open Access 01-06-2008 | Research article

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

Authors: Karen A Dunphy, Anneke C Blackburn, Haoheng Yan, Lauren R O'Connell, D Joseph Jerry

Published in: Breast Cancer Research | Issue 3/2008

Login to get access

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 nulliparous 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 nulliparous 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.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 2007, 57: 43-66.CrossRefPubMed
2.
Clemons M, Goss P: Estrogen and the risk of breast cancer. N Engl J Med. 2001, 344: 276-285. 10.1056/NEJM200101253440407.CrossRefPubMed
3.
4.
MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, Salber EJ, Valaoras VG, Yuasa S: Age at first birth and breast cancer risk. Bull World Health Organ. 1970, 43: 209-221.PubMedPubMedCentral
5.
Rosner B, Colditz GA, Willett WC: Reproductive risk factors in a prospective study of breast cancer: the Nurses' Health Study. Am J Epidemiol. 1994, 139: 819-835.CrossRefPubMed
6.
Sinha DK, Pazik JE, Dao TL: Prevention of mammary carcinogenesis in rats by pregnancy: effect of full-term and interrupted pregnancy. Br J Cancer. 1988, 57: 390-394.CrossRefPubMedPubMedCentral
7.
Sivaraman L, Stephens LC, Markaverich BM, Clark JA, Krnacik S, Conneely OM, O'Malley BW, Medina D: Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. Carcinogenesis. 1998, 19: 1573-1581. 10.1093/carcin/19.9.1573.CrossRefPubMed
8.
Cabanes A, Wang M, Olivo S, deAssis S, Gustafsson JA, Khan G, Hilakivi-Clarke L: Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis. 2004, 25: 741-748. 10.1093/carcin/bgh065.CrossRefPubMed
9.
Grubbs CJ, Farnell DR, Hill DL, McDonough KC: Chemoprevention of N-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17 beta-estradiol and progesterone. J Natl Cancer Inst. 1985, 74: 927-931.PubMed
10.
11.
Thordarson G, Jin E, Guzman RC, Swanson SM, Nandi S, Talamantes F: Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia?. Carcinogenesis. 1995, 16: 2847-2853. 10.1093/carcin/16.11.2847.CrossRefPubMed
12.
Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR: Long-term effect of a first pregnancy on the secretion of prolactin. N Engl J Med. 1987, 316: 229-234.CrossRefPubMed
13.
Bridges RS, Byrnes EM: Reproductive experience reduces circulating 17beta-estradiol and prolactin levels during proestrus and alters estrogen sensitivity in female rats. Endocrinology. 2006, 147: 2575-2582. 10.1210/en.2005-0917.CrossRefPubMed
14.
Russo J, Tay LK, Russo IH: Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat. 1982, 2: 5-73. 10.1007/BF01805718.CrossRefPubMed
15.
Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S: Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. Proc Natl Acad Sci USA. 1999, 96: 2520-2525. 10.1073/pnas.96.5.2520.CrossRefPubMedPubMedCentral
16.
Haslam SZ, Woodward TL: Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. Breast Cancer Res. 2003, 5: 208-215. 10.1186/bcr615.CrossRefPubMedPubMedCentral
17.
Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C: The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci. 2004, 117: 1495-1502. 10.1242/jcs.01000.CrossRefPubMed
18.
McDaniel SM, Rumer KK, Biroc SL, Metz RP, Singh M, Porter W, Schedin P: Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol. 2006, 168: 608-620. 10.2353/ajpath.2006.050677.CrossRefPubMedPubMedCentral
19.
Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, D'Cruz CM, Chodosh LA: Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res. 2006, 66: 6421-6431. 10.1158/0008-5472.CAN-05-4235.CrossRefPubMed
20.
D'Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB, Cox JD, Wang JY, Ha SI, Keister BA, Chodosh LA: Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol. 2002, 16: 2034-2051. 10.1210/me.2002-0073.CrossRefPubMed
21.
Sivaraman L, Conneely OM, Medina D, O'Malley BW: p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc Natl Acad Sci USA. 2001, 98: 12379-12384. 10.1073/pnas.221459098.CrossRefPubMedPubMedCentral
22.
Jerry DJ, Kittrell FS, Kuperwasser C, Laucirica R, Dickinson ES, Bonilla PJ, Butel JS, Medina D: A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene. 2000, 19: 1052-1058. 10.1038/sj.onc.1203270.CrossRefPubMed
23.
Medina D, Kittrell FS: p53 function is required for hormone-mediated protection of mouse mammary tumorigenesis. Cancer Res. 2003, 63: 6140-6143.PubMed
24.
Land CE, Boice JDJ, Shore RE, Norman JE, Tokunaga M: Breast cancer risk from low-dose exposures to ionizing radiation: results of parallel analysis of three exposed populations of women. J Natl Cancer Inst. 1980, 65: 353-376.PubMed
25.
Tokunaga M: Breast cancer among atomic bomb survivors: relationship of prognosis to pathologic findings. Acta Pathol Jpn. 1979, 29: 197-209.PubMed
26.
Minter LM, Dickinson ES, Naber SP, Jerry DJ: Epithelial cell cycling predicts p53 responsiveness to gamma-irradiation during post-natal mammary gland development. Development. 2002, 129: 2997-3008.PubMed
27.
Becker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, Jerry DJ: Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways. Oncogene. 2005, 24: 6345-6353.PubMed
28.
Nichols KE, Malkin D, Garber JE, Fraumeni JF, Li FP: Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001, 10: 83-87.PubMed
29.
Kleihues P, Schauble B, zur HA, Esteve J, Ohgaki H: Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol. 1997, 150: 1-13.PubMedPubMedCentral
30.
Mori N, Yamate J, Umesako S, Hong DP, Okumoto M, Nakao R: Preferential induction of mammary tumors in p53 hemizygous BALB/c mice by fractionated irradiation of a sub-lethal dose of X-rays. J Radiat Res (Tokyo). 2003, 44: 249-254. 10.1269/jrr.44.249.CrossRef
31.
Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, Rehm S, Russo J, Tavassoli FA, Wakefield LM, Ward JM, Green JE: The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene. 2000, 19: 968-988. 10.1038/sj.onc.1203277.CrossRefPubMed
32.
Kuperwasser C, Hurlbut GD, Kittrell FS, Dickinson ES, Laucirica R, Medina D, Naber SP, Jerry DJ: Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice: a model for Li-fraumeni syndrome. Am J Pathol. 2000, 157: 2151-2159.CrossRefPubMedPubMedCentral
33.
Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW: Dissecting p53 tumor suppressor functions in vivo. Cancer Cell. 2002, 1: 289-298. 10.1016/S1535-6108(02)00047-8.CrossRefPubMed
34.
Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D: Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models. Breast Cancer Res. 2007, 9: R12-10.1186/bcr1645.CrossRefPubMedPubMedCentral
35.
Martins CP, Brown-Swigart L, Evan GI: Modeling the therapeutic efficacy of p53 restoration in tumors. Cell. 2006, 127: 1323-1334. 10.1016/j.cell.2006.12.007.CrossRefPubMed
36.
Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007, 445: 656-660. 10.1038/nature05529.CrossRefPubMedPubMedCentral
37.
Colombel M, Radvanyi F, Blanche M, Abbou C, Buttyan R, Donehower LA, Chopin D, Thiery JP: Androgen suppressed apoptosis is modified in p53 deficient mice. Oncogene. 1995, 10: 1269-1274.PubMed
38.
Lynch CJ, Milner J: Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency. Oncogene. 2006, 25: 3463-3470. 10.1038/sj.onc.1209387.CrossRefPubMed
39.
Santarosa M, Ashworth A: Haploinsufficiency for tumour suppressor genes: when you don't need to go all the way. Biochim Biophys Acta. 2004, 1654: 105-122.PubMed
40.
Ma H, Bernstein L, Pike MC, Ursin G: Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies. Breast Cancer Res. 2006, 8: R43-10.1186/bcr1525.CrossRefPubMedPubMedCentral
41.
Lin SC, Lee KF, Nikitin AY, Hilsenbeck SG, Cardiff RD, Li A, Kang KW, Frank SA, Lee WH, Lee EY: Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis. Cancer Res. 2004, 64: 3525-3532. 10.1158/0008-5472.CAN-03-3524.CrossRefPubMed
42.
Lewandowski SA, Thiery J, Jalil A, Leclercq G, Szczylik C, Chouaib S: Opposite effects of estrogen receptors alpha and beta on MCF-7 sensitivity to the cytotoxic action of TNF and p53 activity. Oncogene. 2005, 24: 4789-4798. 10.1038/sj.onc.1208595.CrossRefPubMed
43.
Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM: Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res. 2007, 67: 7746-7755. 10.1158/0008-5472.CAN-06-3724.CrossRefPubMed
44.
Matulka LA, Triplett AA, Wagner KU: Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol. 2007, 303: 29-44. 10.1016/j.ydbio.2006.12.017.CrossRefPubMed
45.
Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH: An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development. 2002, 129: 1377-1386.PubMed
46.
Britt K, Ashworth A, Smalley M: Pregnancy and the risk of breast cancer. Endocr Relat Cancer. 2007, 14: 907-933. 10.1677/ERC-07-0137.CrossRefPubMed
47.
Reichmann E, Ball R, Groner B, Friis RR: New mammary epithelial and fibroblastic cell clones in coculture form structures competent to differentiate functionally. J Cell Biol. 1989, 108: 1127-1138. 10.1083/jcb.108.3.1127.CrossRefPubMed
48.
Wicha MS: Interaction of rat mammary epithelium with extracellular matrix components. Prog Clin Biol Res. 1984, 145: 129-142.PubMed
49.
Maffini MV, Calabro JM, Soto AM, Sonnenschein C: Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. Am J Pathol. 2005, 167: 1405-1410.CrossRefPubMedPubMedCentral
50.
Taddei I, Faraldo MM, Teuliere J, Deugnier MA, Thiery JP, Glukhova MA: Integrins in mammary gland development and differentiation of mammary epithelium. J Mammary Gland Biol Neoplasia. 2003, 8: 383-394. 10.1023/B:JOMG.0000017426.74915.b9.CrossRefPubMed
51.
Woodward TL, Mienaltowski AS, Modi RR, Bennett JM, Haslam SZ: Fibronectin and the alpha(5)beta(1) integrin are under developmental and ovarian steroid regulation in the normal mouse mammary gland. Endocrinology. 2001, 142: 3214-3222. 10.1210/en.142.7.3214.CrossRefPubMed
52.
Faraldo MM, Deugnier MA, Thiery JP, Glukhova MA: Growth defects induced by perturbation of beta1-integrin function in the mammary gland epithelium result from a lack of MAPK activation via the Shc and Akt pathways. EMBO Rep. 2001, 2: 431-437.CrossRefPubMedPubMedCentral
Metadata
Title
Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/-mice
Authors
Karen A Dunphy
Anneke C Blackburn
Haoheng Yan
Lauren R O'Connell
D Joseph Jerry
Publication date
01-06-2008
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2008
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2094

Other articles of this Issue 3/2008

Breast Cancer Research 3/2008 Go to the issue

Research article

Surface-enhanced laser desorption/ionization time-of-flight proteomic profiling of breast carcinomas identifies clinicopathologically relevant groups of patients similar to previously defined clusters from cDNA expression

Research article

PMC42, a breast progenitor cancer cell line, has normal-like mRNA and microRNA transcriptomes

Research article

Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort

Research article

Intact and total insulin-like growth factor-binding protein-3 (IGFBP-3) levels in relation to breast cancer risk factors: a cross-sectional study

Letter

The future of mammary stem cell biology: the power of in vivo transplants

Review

Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits