Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

Guzman, Raphaël; Yang, Jason; Lakshmanaswamy, Rajkumar; Thórdarson, Gudmundur; Chen, Xiaoyan; Nandi, Satyabrata

doi:10.1073/pnas.96.5.2520

Cited by 194 publications

(152 citation statements)

References 15 publications

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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: 97%

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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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mentioning

confidence: 97%

“…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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“…Even more, there is a suggestion that pregnancy might have a protective effect [8,9]. Several theories have been posed to explain this finding including patient selection, the healthy mother effect [9], alloimmunization [10] and estrogen-induced apoptosis of the endocrine responsive breast cancer cells [11]. Pregnancy is now generally deemed safe 1-2 years following breast cancer diagnosis [7].…”

Section: Pregnancy After Breast Cancermentioning

confidence: 99%

Breast-feeding after breast cancer: if you wish, madam

Azim

Bellettini²,

Gelber

et al. 2008

Breast Cancer Res Treat

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Breast cancer is the most common malignant tumor-affecting women during the child bearing period. With the rising trend in delaying pregnancy later in life, the issue of subsequent pregnancy and lactation following breast cancer diagnosis has been more frequently encountered. In this context, data is scarce particularly those addressing the issue of lactation. In this review, we discussed different endocrinal, clinical and biological aspects dealing with breast-feeding after breast cancer in an attempt to determine how safe and feasible this approach is.

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“…Like humans, parous rats and mice have a greatly reduced susceptibility to chemically induced mammary tumorigenesis compared to their nulliparous siblings [3]. Humans who carry germ line mutations in tumor susceptibility genes do not benefit from the protective effects of pregnancy, but have a significantly greater risk of developing the disease following one or multiple gestation cycles [4].…”

Section: Pregnancy and Breast Cancermentioning

confidence: 99%

Stem Cells, Hormones, and Mammary Cancer

Smith¹

2008

Hormonal Carcinogenesis V

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Pregnancy and breast cancerThe incidence of breast cancer is influenced by age, genetics, ethnicity, diet, socioeconomic status, and reproductive history. The latter is the strongest and most reliable risk factor besides age and genetic susceptibility [1]. Reproductive factors have been associated with risk for breast cancer since the 17 th century, when the disease was noted to be more prevalent among Catholic nuns. It is now a well-established fact that a full-term pregnancy early in life is associated with a long-term risk reduction for developing breast cancer. A woman who has her first child after the age of 35 has approximately twice the risk of developing breast cancer as a woman who has a child before age 20 (see current NCI Cancer Fact Sheet on Pregnancy and Breast Cancer Risk). Despite this long-term reduction in breast cancer risk in parous women, epidemiologists agreed at a recent NCI-sponsored workshop on "Early Reproductive Events and Breast Cancer" (http://nci.nih.gov/cancerinfo/ere) that each gestation increases temporarily the likelihood for developing breast cancer [2]. This transient increase in breast cancer risk lasts for a few years after a full-term pregnancy.Pregnancy has a very similar dual effect on the etiology of mammary cancer in animal models. Like humans, parous rats and mice have a greatly reduced susceptibility to chemically induced mammary tumorigenesis compared to their nulliparous siblings [3]. Humans who carry germ line mutations in tumor susceptibility genes do not benefit from the protective effects of pregnancy, but have a significantly greater risk of developing the disease following one or multiple gestation cycles [4]. There are, however, conflicting reports whether lactation influences the onset of breast cancer in women with BRCA1 mutations. The current view on breast cancer as a stem cell disease is founded on compelling evidence that many breast cancers may arise as clonal expansions from epithelial progenitors with an infinite lifespan [5]. It has been hypothesized that unique properties of mammary stem cells, such as self-renewal, make this population a prime target for transformation and tumorigenesis. Several experimental breast cancer models support this hypothesis. The most venerable is the mammary tumor virus [6] model in mice, where MMTV proviral insertions produce mutated mammary cells, which attain immortality (escape from growth senescence) and produce clones of mammary cells with increased propensity to develop mammary cancer. Serial transplantations of these preneoplastic lesions result in the formation of hyperplastic/dysplastic ductal trees, suggesting that multipotent cells are affected by MMTV transformation and that they pass on their neoplastic properties to their descendants [7]. Morphologically undifferentiated cells,

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Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

Cited by 194 publications

References 15 publications

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

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

Breast-feeding after breast cancer: if you wish, madam

Stem Cells, Hormones, and Mammary Cancer

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