Breast Cancer Prevention: Lessons to be Learned from Mechanisms of Early Pregnancy–Mediated Breast Cancer Protection

Meier-Abt, Fabienne; Bentires‐Alj, Mohamed; Rochlitz, Christoph

doi:10.1158/0008-5472.can-14-2717

Cited by 28 publications

(13 citation statements)

References 24 publications

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“…Clearly, to this end further studies are still needed to elucidate the mechanisms of parity-mediated breast cancer protection. Recently, for instance, alterations in Wnt and TGFβ signaling pathways in mammary stem/progenitor cells have revealed new potential targets for preventive interventions [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Parity improves anti-tumor immunity in breast cancer patients

et al. 2017

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Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor-associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy.To this end, we collected peripheral blood from healthy nulliparous, primigravid and parous women, as well as from breast cancer patients. IFN-γ ELISpot assays were performed to measure the intensity and specificity of T cell responses against 11 different TAA. The impact of TAA-specific Treg cells on anti-TAA responses was assessed by performing the assay before and after depletion of CD4+CD25+ T cells. The antigenic specificities of these Treg cells were analyzed by the Treg specificity assay. Furthermore, we conducted flow cytometric analyses to determine the memory phenotype and cytokine secretion profile of TAA-specific T cells.Our results demonstrate that pregnancy induces functional and long-lived memory and effector T cells that react against multiple TAA. These persist for many decades in parous females, but are not found in age-matched females without children. We also detected TAA-specific Treg cells, which suppressed strong effector T cell responses after delivery. Nulliparous breast cancer patients displayed median TAA-specific effector T cell responses to be decreased threefold compared to parous patients, which could be restored in vitro after depletion of Treg cells.

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Section: Discussionmentioning

confidence: 99%

Parity improves anti-tumor immunity in breast cancer patients

et al. 2017

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“…Nulliparity and an older age at first birth were associated with increased percent density in both premenopausal and postmenopausal women in a study of 1,900 women by Vachon et al [21]. Changes in the cellular processes in the breast tissue during pregnancy have been suggested as possible mechanisms behind protective effect of pregnancy on breast cancer risk [39]. Pregnancy results in reduction in the number of stem cells which are responsible for life-long decrease in the mammary stem cell numbers in parous women, and thus a decrease in the pool of potentially transformable susceptible epithelial cells [16].…”

Section: Discussionmentioning

confidence: 99%

Reproductive factors related to childbearing and mammographic breast density

Yaghjyan

Colditz

Rosner

et al. 2016

Breast Cancer Res Treat

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Purpose We investigated the associations of reproductive factors related to childbearing with percent breast density, absolute dense and non-dense areas, by menopausal status. Methods This study included 4,110 cancer-free women within the Nurses’ Health Study and Nurses’ Health Study II cohorts. Percent breast density, absolute dense and non-dense areas were measured from digitized mammography film images with computerized techniques. All density measures were square root-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires, at the time of the mammogram date. Results As compared to nulliparous women, parous postmenopausal women had lower percent density (β= −0.60, 95% CI −0.84; −0.37), smaller absolute dense area (β= −0.66, 95% CI −1.03; −0.29), and greater non-dense area (β=0.72, 95% CI 0.27; 1.16). Among parous women, number of children was inversely associated with percent density in pre- (β per one child=−0.12, 95% CI −0.20; −0.05) and postmenopausal women (β per one child=−0.07, 95% CI −0.12; −0.02). The positive associations of breastfeeding with absolute dense and non-dense areas were limited to premenopausal women, while the positive association of the age at first child’s birth with percent density and the inverse association with non-dense area were limited to postmenopausal women. Conclusions Women with greater number of children and younger age at first child’s birth have more favorable breast density patterns that could explain subsequent breast cancer risk reduction.

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“…Breast tissue changes during pregnancy have been suggested as possible reasons for the long-term protective effect on breast cancer risk [30]. The in uence of full term pregnancy on the breast tissue appears to be complex and some of the suggested mechanisms include changes in hormonal signaling in the breast, gene methylation and expression changes, long-term reduction in the levels of circulating hormones, and life-long reduction in the number of mammary stem cells [4,[31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Associations of reproductive breast cancer risk factors with breast tissue composition

Yaghjyan

Austin-Datta

Oh³

et al. 2020

Preprint

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Background We investigated the associations of reproductive factors with percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples. Methods This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses’ Health Study and Nurses’ Health Study II cohorts. Percentage of each tissue type (epithelium stroma, and fat) was measured on whole section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with percentage of tissue types, while adjusting for known breast cancer risk factors. Results As compared to parous women, nulliparous women had a smaller percentage of epithelium (β= -0.26, 95% confidence interval [CI] -0.41, -0.11) and fat (β= -0.34, 95% CI -0.54, -0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, number of children was inversely associated with percentage of stroma (β per child= -0.01 (-0.02, -0.00). Duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β= -0.30, 95% CI -0.54, -0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma. Conclusions Our findings suggest that reproductive factors with a protective effect on breast cancer risk may be associated with a greater proportion of epithelium and a smaller proportion of stroma, potentially suggesting importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

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Breast Cancer Prevention: Lessons to be Learned from Mechanisms of Early Pregnancy–Mediated Breast Cancer Protection

Cited by 28 publications

References 24 publications

Parity improves anti-tumor immunity in breast cancer patients

Parity improves anti-tumor immunity in breast cancer patients

Reproductive factors related to childbearing and mammographic breast density

Associations of reproductive breast cancer risk factors with breast tissue composition

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