Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2

Jernström, Helena; Lerman, Caryn; Ghadirian, Parviz; Lynch, Henry T.; Weber, Barbara; Garber, Judy E.; Daly, Mary B.; Olopade, Olufunmilayo I.; Foulkes, William D.; Warner, Ellen; Brunet, Jean‐Sébastien; Narod, Steven A.

doi:10.1016/s0140-6736(99)04336-6

Cited by 196 publications

(101 citation statements)

References 22 publications

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“…In that study, the IGF-1 levels of parous and nulliparous women were similar. Furthermore, we found that the frequency of the IGF1-19/-19 genotype was significantly higher among known BRCA1 carriers compared with other high-risk women and we have reported previously that each pregnancy up to three confers an increased risk for breast cancer before age 40 years among BRCA1 and BRCA2 carriers (Jernström et al, 1999). We therefore hypothesise that the IGF-1 levels do not decrease post-partum in women with the IGF1-19/-19 genotype.…”

Section: Igf1-19/-mentioning

confidence: 47%

Absence of the common Insulin-like growth factor-1 19-repeat allele is associated with early age at breast cancer diagnosis in multiparous women

et al. 2007

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Multiparity decreases the risk of breast cancer in white women, whereas it is a risk factor in black women o50 years. Early-onset breast cancer (o50 years) has been associated with high insulin-like growth factor-1 (IGF-1) levels. Absence of the common IGF1 19 cytosine-adenine (CA)-repeat allele (IGF1-19/-19) inverts the effect of several non-genetic factors on breast cancer risk but the interaction between IGF1-19/-19 and multiparity on breast cancer risk is unknown. As IGF1-19/-19, multiparity and early-onset breast cancer are more common in black than in white women, we aimed to study whether multiparity combined with IGF1-19/-19 increases the risk of early-onset breast cancer. Four hundred and three breast cancer patients diagnosed in Lund, Sweden, at age 25 -99 years were genotyped for the IGF1 CA-repeat length using fragment analysis. Overall, 12.9% carried the IGF1-19/-19 genotype. There was a highly significant interaction between multiparity and IGF1-19/-19 on age at breast cancer diagnosis (P ¼ 0.007). Among IGF1-19/-19 patients, multiparity was associated with a 9.2 year earlier age at diagnosis compared with uniparity or nulliparity (P ¼ 0. Breast cancer is the most common malignancy in women worldwide (Parkin et al, 2001(Parkin et al, , 2002. Approximately 10% of women living in Sweden will develop the disease during their lifetime. The median age at breast cancer diagnosis in women in Sweden is 60 years; approximately 4% of women are 40 years or younger at diagnosis (data from the Swedish Cancer Registry). The prognosis is often poorer in younger than in older women (Sidoni et al, 2003) in terms of overall survival and relapse (Han et al, 2004), partly because young women do not benefit from breast cancer screening and early-onset breast cancers are usually detected clinically at a more advanced stage. In Lund, Sweden, mammography screening is initiated at age 45 years and is performed every 18 months until the age of 74 years. As of today, no tests are routinely performed to identify the subgroup of women who do not belong to high-risk breast cancer families (eg BRCA1 families) but who would nevertheless benefit from breast cancer screening at an earlier age owing to an increased risk for early-onset breast cancer.Breast cancer risk is determined by genetic factors and nongenetic factors, for example, reproductive factors (Beral and Reeves, 1993;Kelsey et al, 1993). An increased age at first full-term pregnancy and low parity have been associated with an increased risk of developing breast cancer in the developed world (Kelsey et al, 1993). In the short term, a first full-term pregnancy increases the risk of breast cancer (Beral and Reeves, 1993). Each subsequent live-birth reportedly decreases the risk of breast cancer by 30% and after three full-term pregnancies, the short-term risk of developing breast cancer is similar to the risk of nulliparous women (McCredie et al, 1998). In the long-term, a full-term pregnancy confers a decreased risk of developing breast cancer (McCredie et al, 1998) and ...

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Section: Igf1-19/-mentioning

confidence: 47%

Absence of the common Insulin-like growth factor-1 19-repeat allele is associated with early age at breast cancer diagnosis in multiparous women

et al. 2007

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“…With respect to parity, this study revealed no difference in mean number of pregnancies between mutation carriers with and without breast cancer. An earlier study from the same group suggested that the risk of breast cancer prior to age 40 in BRCA1/2 carriers increased with increasing number of births (Jernstrom et al 1999). While the findings from this study are provocative, the number of participants was small and likely included some of the same women as were included in the later larger analysis that showed no association between parity and breast cancer risk (Jernstrom et al 2004).…”

Section: Parity and Age At First Full-term Pregnancymentioning

confidence: 68%

“…However, the majority of studies have found no significant differences in age at menarche amongst BRCA1 carriers who developed breast cancer as compared with those who had not (Jernstrom et al 1999, Rebbeck et al 2001. Thus, in contradistinction to what is observed in the general population, these studies have not demonstrated that early age at menarche influences breast cancer risk in mutation carriers.…”

Section: Age At Menarchementioning

confidence: 99%

BRCA1 in hormonal carcinogenesis: basic and clinical research

Rosen¹,

Fan²,

Isaacs³

2005

Endocr Relat Cancer

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The breast and ovarian cancer susceptibility gene-1 (BRCA1) located on chromosome 17q21 encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. The observation that most BRCA1 mutant breast cancers are hormone receptor negative has led some to question whether hormonal factors contribute to the etiology of BRCA1-mutant breast cancers. Nevertheless, the caretaker function of BRCA1 is a generic one and does not explain why BRCA1 mutations confer a specific risk for tumor types that are hormoneresponsive or that hormonal factors contribute to the etiology, including those of the breast, uterus, cervix, and prostate. An accumulating body of research indicates that in addition to its wellestablished roles in regulation of the DNA damage response, the BRCA1 protein interacts with steroid hormone receptors (estrogen receptor (ER-a) and androgen receptor (AR)) and regulates their activity, inhibiting ER-a activity and stimulating AR activity. The ability of BRCA1 to regulate steroid hormone action is consistent with clinical-epidemiological research suggesting that: (i) hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers; and (ii) the spectrum of risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that observed in the general population. These data suggest a model for BRCA1 carcinogenesis in which genomic instability leads to the initiation of cancerous cell clones, while loss of normal restraint on hormonal stimulation of mammary epithelial cell proliferation allows amplification of these pre-existing clones. Further research will be required to substantiate this hypothesis.

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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]. There are, however, conflicting reports whether lactation influences the onset of breast cancer in women with BRCA1 mutations.…”

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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Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2

Cited by 196 publications

References 22 publications

Absence of the common Insulin-like growth factor-1 19-repeat allele is associated with early age at breast cancer diagnosis in multiparous women

Absence of the common Insulin-like growth factor-1 19-repeat allele is associated with early age at breast cancer diagnosis in multiparous women

BRCA1 in hormonal carcinogenesis: basic and clinical research

Stem Cells, Hormones, and Mammary Cancer

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