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      Inherited factors contribute to an inverse association between preeclampsia and breast cancer

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          Abstract

          Background

          Preeclampsia is frequently linked to reduced breast cancer risk. However, little is known regarding the underlying genetic association and the association between preeclampsia and mammographic density.

          Methods

          This study estimates the incidence rate ratios (IRRs) of breast cancer in patients with preeclampsia, when compared to women without preeclampsia, using Poisson regression models in two cohorts of pregnant women: a Swedish nationwide cohort (n = 1,337,934, 1973–2011) and the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, n = 55,044, 1958–2015). To identify the genetic association between preeclampsia and breast cancer, we used logistic regression models to calculate the odds ratios (ORs) of preeclampsia in sisters of breast cancer patients, and in women with different percentiles of breast cancer polygenic risk scores (PRS). Linear regression models were used to estimate the mammographic density by preeclampsia status in the KARMA cohort.

          Results

          A decreased risk of breast cancer was observed among patients with preeclampsia in both the nationwide (IRR = 0.90, 95% CI = 0.85; 0.96) and KARMA cohorts (IRR = 0.75, 95% CI = 0.61; 0.93). Women with high breast cancer PRS and sisters of breast cancer patients had a lower risk of preeclampsia (OR = 0.89, 95% CI = 0.83; 0.96). Mammographic density was lower in women with preeclampsia compared to women without preeclampsia (-2.04%, 95% CI = -2.65; -1.43). Additionally, among sisters in the KARMA cohort (N = 3500), density was lower in sisters of patients with preeclampsia compared to sisters of women without preeclampsia (-2.76%, 95% CI = -4.96; -0.56).

          Conclusion

          Preeclampsia is associated with reduced risk of breast cancer and mammographic density. Inherited factors contribute to this inverse association.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13058-017-0930-6) contains supplementary material, which is available to authorized users.

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          Most cited references33

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          Circulating angiogenic factors and the risk of preeclampsia.

          Richard J. Levine, Sharon E. Maynard, Cong Qian … (2004)
          The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society
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            Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.

            S E Hankinson, W Willett, G. A. Colditz … (1998)
            Insulin-like growth factor (IGF)-I, a mitogenic and antiapoptotic peptide, can affect the proliferation of breast epithelial cells, and is thought to have a role in breast cancer. We hypothesised that high circulating IGF-I concentrations would be associated with an increased risk of breast cancer. We carried out a nested case-control study within the prospective Nurses' Health Study cohort. Plasma concentrations of IGF-I and IGF binding protein 3 (IGFBP-3) were measured in blood samples collected in 1989-90. We identified 397 women who had a diagnosis of breast cancer after this date and 620 age-matched controls. IGF-I concentrations were compared by logistic regression with adjustment for other breast-cancer risk factors. There was no association between IGF-I concentrations and breast-cancer risk among the whole study group. In postmenopausal women there was no association between IGF-I concentrations and breast-cancer risk (top vs bottom quintile of IGF-I, relative risk 0.85 [95% CI 0.53-1.39]). The relative risk of breast cancer among premenopausal women by IGF-I concentration (top vs bottom tertile) was 2.33 (1.06-5.16; p for trend 0.08). Among premenopausal women less than 50 years old at the time of blood collection, the relative risk was 4.58 (1.75-12.0; p for trend 0.02). After further adjustment for plasma IGFBP-3 concentrations these relative risks were 2.88 and 7.28, respectively. A positive relation between circulating IGF-I concentration and risk of breast cancer was found among premenopausal but not postmenopausal women. Plasma IGF-I concentrations may be useful in the identification of women at high risk of breast cancer and in the development of risk reduction strategies. Additional larger studies of this association among premenopausal women are needed to provide more precise estimates of effect.
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              A quality study of a medical birth registry.

              S Cnattingius, A. ERICSON, J Gunnarskog … (1990)
              A quality control study was made of the Swedish Medical Birth Registry. This registry used one mode of data collection during 1973-1981 and another from 1982 onwards. The number of errors in the register was checked by comparing register information with a sample of the original medical records, and the variability in the use of diagnoses between hospitals was studied. Different types of errors were identified and quantified and the efficiency of the two methods of data collection evaluated.
              Article 0 comments Cited 202 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Haomin Yang:
                ORCID: http://orcid.org/0000-0002-2252-2606
                0046-852482313 , haomin.yang@ki.se
                Wei He: wei.he@ki.se
                Mikael Eriksson: mikael.eriksson@ki.se
                Jingmei Li: jingmei.li@ki.se
                Natalie Holowko: natalie.holowko@ki.se
                Flaminia Chiesa: flaminia.chiesa@ki.se
                Per Hall: per.hall@ki.se
                Kamila Czene: kamila.czene@ki.se
                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Journal ID (iso-abbrev): Breast Cancer Res
                Title: Breast Cancer Research : BCR
                Publisher: BioMed Central (London )
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Electronic): 23 January 2018
                Publication date PMC-release: 23 January 2018
                Publication date (Print): 2018
                Volume: 20
                Electronic Location Identifier: 6
                Affiliations
                [1 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, ; SE-17177 Stockholm, Sweden
                [2 ]ISNI 0000 0004 0620 715X, GRID grid.418377.e, Genome Institute of Singapore, ; 138672 Singapore, Singapore
                [3 ]Department of Oncology, South General Hospital, SE-11883 Stockholm, Sweden
                Author information
                http://orcid.org/0000-0002-2252-2606
                Article
                Publisher ID: 930
                DOI: 10.1186/s13058-017-0930-6
                PMC ID: 5782395
                PubMed ID: 29361985
                SO-VID: 6e689792-31f6-49fb-b937-19862d31c225
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 6 September 2017
                Date accepted : 28 December 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: 2014 -2271
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002794, Cancerfonden;
                Award ID: CAN 2016/684
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100006636, Forskningsrådet om Hälsa, Arbetsliv och Välfärd;
                Award ID: 2016-00081
                Award Recipient :
                Funded by: Märit and Hans Rausing’s Initiative against Breast Cancer
                Funded by: FundRef http://dx.doi.org/10.13039/501100004543, China Scholarship Council;
                Award ID: 201406010275
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007435, Åke Wiberg Stiftelse;
                Funded by: Ollie och Elof Ericssons Foundation for Scientific Research
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast cancer,preeclampsia,mammographic density
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast cancer, preeclampsia, mammographic density

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