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?

Thórdarson, Gudmundur; Jin, Edward; Guzman, Raphaël; Swanson, Steven M.; Nandi, Satyabrata; Talamantes, Frank

doi:10.1093/carcin/16.11.2847

Cited by 110 publications

(114 citation statements)

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“…Furthermore, this trend was not observed in the p53 þ /À mice without a transgene. Although parity appears to reduce the risk of mammary carcinoma in the p53 þ /À mice without the transgene, in agreement with expectations from studies in rodents and humans (Moon, 1969;Swanson et al, 1995;Thordarson et al, 1995;Hamilton and Mack, 2003), this protection was negated in T380A mice and dramatically reversed in p53 þ /À T380A mice.…”

Section: Resultssupporting

confidence: 87%

“…Parity is known to modulate the risk of mammary tumorigenesis in both humans and rodents (Moon, 1969;Thordarson et al, 1995;Hamilton and Mack, 2003). In mice, it has been demonstrated that parity protects against mammary carcinogenic insult and that the effects of the carcinogen are dependent upon the mitogenic environment at the time of insult; the beneficial effect of parity is reversed by prolactin stimulation from pituitary isografts.…”

Section: Discussionmentioning

confidence: 99%

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Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

et al. 2006

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Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

et al. 2006

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“…If the ERα-positive cell population is reduced, the number of cell divisions driven by estrogen and the potential development and progression of cancer should be reduced. A decrease in ERα expression after pregnancy has been described in animal models, and in the human breast, there is immunohistochemical evidence for decreased ERα expression in undifferentiated breast lobules that are associated with the nulliparous state (40,41). However, the observation, on the mRNA level, that this reduction occurs soon after pregnancy and that it persists is novel.…”

Section: Discussionmentioning

confidence: 96%

Gene Expression Patterns in the Human Breast after Pregnancy

Asztalos

Gann

Hayes

et al. 2010

Cancer Prevention Research

118

117

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Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammationassociated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor α (ERα, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-β (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk. Cancer Prev Res; 3(3); 301-11. ©2010 AACR.

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“…In particular, there is strong epidemiological evidence that women who experience a full-term pregnancy early in their lives have a significantly reduced risk for developing breast cancer (3)(4)(5). This is recapitulated in rat models that demonstrate that early full-term pregnancy confers resistance to chemical carcinogen-induced mammary tumorigenesis (6)(7)(8)(9)(10)(11). This protection can be mimicked with the hormones estrogen (E) and progesterone (P; refs.…”

mentioning

confidence: 99%

“…The utility of the rodent models in which a defined hormonal regimen can be used to mimic the protective effect of pregnancy is well documented (9)(10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis

Sivaraman

Conneely

Medina

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

102

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Full-term pregnancy early in reproductive life is protective against breast cancer in women. Pregnancy also provides protection in animals against carcinogen-induced breast cancer, and this protection can be mimicked by using the hormones estrogen and progesterone. The molecular mechanisms that form the basis for this protective effect have not been elucidated. On the basis of our results, we propose a cell-fate hypothesis. At a critical period in adolescence the hormonal milieu of pregnancy affects the developmental fate of a subset of mammary epithelial cells and its progeny, which results in persistent differences in molecular pathways between the epithelial cells of hormone-treated and mature virgin mammary glands. These changes in turn dictate the proliferative response to carcinogen challenge and include a block in carcinogen-induced increase in mammary epithelial cell proliferation and an increased and sustained expression of nuclear p53 in the hormone-treated mammary gland. This hormone-induced nuclear p53 is transcriptionally active as evidenced by increased expression of mdm2 and p21 (CIP1͞WAF1). Importantly, exposure to perphenazine, a compound that induces mammary gland differentiation but does not confer protection, does not induce p53 expression, indicating that p53 is not a differentiation marker. The proliferative block and induction of p53 are operative in both rats and mice, results that support the generality of the proposed hypothesis.T he lifetime risk of developing breast cancer among Western women is Ϸ10%, and despite advances in therapeutic strategies, breast cancer remains the leading cause of cancer deaths in women in most developed countries (1). Prevention of the disease can be achieved with better understanding of the etiological factors contributing to the development of the disease. There is significant evidence that the timing of normal developmental events like menarche, menopause, and age of first parity have a significant impact on an individual's susceptibility to breast cancer (2, 3). In particular, there is strong epidemiological evidence that women who experience a full-term pregnancy early in their lives have a significantly reduced risk for developing breast cancer (3-5). This is recapitulated in rat models that demonstrate that early full-term pregnancy confers resistance to chemical carcinogen-induced mammary tumorigenesis (6-11). This protection can be mimicked with the hormones estrogen (E) and progesterone (P; refs. 9 and 12) or human CG (13) given either before or immediately after carcinogen challenge to induce a refractory state.Despite a wealth of literature supporting the role of endocrinological processes in mediating parity-related refractoriness, the cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved. The utility of the rodent models in which a defined hormonal regimen can be used to mimic the protective effect of pregnancy is well documented (9-17).Differing hypotheses to explain the protective effects have ...

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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?

Cited by 110 publications

References 0 publications

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Gene Expression Patterns in the Human Breast after Pregnancy

p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis

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