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. Author manuscript; available in PMC: 2025 Jan 1.
Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2024 Jul 1;33(7):933–943. doi: 10.1158/1055-9965.EPI-23-1567

Associations of early-life and adult anthropometric measures with the expression of stem cell markers CD44, CD24, and ALDH1A1 in women with benign breast biopsies

Hannah Oh 1,2, Lusine Yaghjyan 3,*, Yujing J Heng 4, Bernard Rosner 5, Matt B Mahoney 5, Divya Murthy 5, Gabrielle M Baker 4, Rulla M Tamimi 6,*
PMCID: PMC11216865  NIHMSID: NIHMS1990174  PMID: 38652503

Abstract

Background:

According to the stem cell hypothesis, breast carcinogenesis may be related to the breast stem cell pool size. However, little is known about associations of breast cancer risk factors, such as anthropometric measures, with the expression of stem cell markers in non-cancerous breast tissue.

Methods:

The analysis included 414 women with biopsy-confirmed benign breast disease (BBD) in the Nurses’ Health Study (NHS) and NHSII. Birthweight, weight at age 18, current weight, and current height were reported via self-administered questionnaire. Immunohistochemical staining of stem cell markers (CD44, CD24, ALDH1A1) in histopathologically normal epithelial and stromal breast tissue was quantified with an automated computational image analysis system. Linear regression was used to examine the associations of early-life and adult anthropometric measures with log-transformed stem cell marker expression, adjusting for potential confounders.

Results:

Birthweight (≥10.0 vs. <5.5 lbs: β [95% CI]=4.29 [1.02, 7.56]; p-trend=0.001 in stroma) and adult height (≥67.0 vs. <63.0 inch: 0.86 [0.14, 1.58]; p-trend=0.02 in epithelium and stroma combined) were positively associated with CD44 expression. Childhood body fatness was inversely (p-trend=0.03) and adult height was positively associated with CD24 expression in combined stroma and epithelium (p-trend=0.03).

Conclusion:

Our data suggest that anthropometric measures, such as birthweight, adult height, and childhood body fatness, may be associated with the stem cell expression among women with BBD.

Impact:

Anthropometric measures, such as birthweight, height, and childhood body fatness, may have long-term impacts on stem cell population in the breast.

INTRODUCTION

Several early-life and adult anthropometric measures are associated with breast cancer risk. Birthweight (1,2), height (3,4), and postmenopausal body fatness (5,6) are positively associated with breast cancer risk, whereas early-life and young adult body fatness (7-9) are inversely associated with both pre- and post-menopausal breast cancer risks. Although the exact mechanisms through which these factors influence breast cancer risk are not fully understood, studies have shown associations of these factors with intermediate risk markers, such as mammographic density (10-12) and texture (11), breast tissue composition (13), and breast tissue proliferation marker expression (e.g., Ki67) (14). These findings suggest the potential effects of early-life and adult anthropometric measures on breast tissue carcinogenesis.

Breast tissue architecture is maintained by breast stem cells, which have self-renewal capacity and play a critical role in tissue repair and remodeling (15). In the mammary gland, stem cells are also the only cell subpopulation that can accumulate all the oncogenic alterations (16). Further, because cancer is a disease characterized by uncontrolled growth and spread of abnormal cells, dysregulation of self-renewing stem cells is likely to be involved in breast carcinogenesis (17). The stem cell hypothesis of breast cancer suggests that the amount and activity of stem cell population are positively related to breast cancer risk (18,19). This hypothesis also proposes that the number of mammary tissue-specific stem cells is likely to be determined early in life (20) and that exposure to hormones that stimulate breast proliferation (e.g., estrogens, insulin-like growth factor [IGF-1]) (21-23) may influence the replication rates of these stem cells. In breast tumors, higher expression levels of stem cell markers have been associated with unfavorable tumor characteristics and poor prognosis (24-28). However, little is known about the relationships of early-life and adult anthropometric measures with the number and activity of stem cells in the breast tissue of cancer-free women.

In this study, we examined the associations of early-life and adult anthropometric measures (birthweight, childhood and adult body fatness, and height) with well-characterized, validated stem cell marker expressions (CD44, CD24, aldehyde dehydrogenase family 1 member A1 [ALDH1A1]) in histopathologically normal breast tissue among women with benign breast disease (BBD). Stem cell marker CD44 and CD24 have been linked to distant metastasis and poor survival in breast tumors (24-26). Another stem cell marker, ALDH1A1, is correlated with tumor size, histological grade, and chemotherapy resistant breast cancer (27,28). The investigation of risk factor associations with these stem cell marker expression in cancer-free women may provide additional insights into the link between these risk factors and breast cancer risk.

MATERIALS AND METHODS

Study population

This study included women with biopsy-confirmed BBD who participated in a nested case-control study of breast cancer within the Nurses’ Health Study (NHS) and NHSII. The NHS and NHSII are ongoing cohort studies of female registered nurses that began in 1976 (aged 30-55 years) and 1989 (aged 25-42 years), respectively. For both cohorts, information on demographics, medical histories, health risk factors, and disease diagnosis (including BBD) were collected via self-administered questionnaires (29). A nested case-control study of breast cancer was conducted among women with biopsy-confirmed BBD. Details of this nested case-control study have been previously described (30,31). Briefly, cases were women who developed breast cancer (through 1998 in the NHS; through 1999 in the NHSII) following their biopsy-confirmed BBD diagnosis. At the time each case was diagnosed, up to four controls were selected among women who remained free of breast cancer, matching to the case on the year of birth and year of benign breast biopsy. For all cases and controls, we attempted to obtain BBD pathology records and archived benign breast biopsy specimen from their hospital pathology departments. Characteristics of women with and without biopsy specimen were similar (13). To account for clinical and subclinical tissue change, we restricted the study to participants who were cancer-free (without in situ or invasive breast carcinoma) at the time of benign breast biopsy. At the end, a total of 414 women (349 from the NHS and 65 from the NHSII; 86 cases and 328 controls) with histopathologically normal breast tissue with evaluable staining were included in this study. In sensitivity analysis, we repeated the analyses after restricting the population to controls (n=328). The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Consent was obtained or implied by return of questionnaires.

Anthropometric measures

Participants reported birthweight, body fatness at ages 5 and 10 years, adult height, weight at age 18, and current weight via self-administered questionnaires. Birthweight (lbs) was reported in 1991 (NHSII) and 1992 (NHS). Body fatness at ages 5 and 10 years were recalled in 1988 (NHS) and 1989 (NHSII) using Stunkard’s nine-level pictogram (level 1: most lean; level 9: most overweight) (32). In an independent study, recalled body fatness using a pictogram demonstrated a good correlation with BMI measured at approximately the similar ages (Pearson r =0.60-0.66) (33). We estimated childhood body fatness by calculating average body fatness at ages 5 and 10 years. We collapsed extreme categories with few cell counts. Adult height and weight at age 18 were reported via the baseline questionnaire. We estimated BMI at age 18 (kg/m2) by dividing weight at age 18 by adult height. We estimated current adult BMI (kg/m2) using current weight that was reported around the time of benign breast biopsy. We estimated change in BMI since age 18 (kg/m2) by subtracting BMI at age 18 from current adult BMI.

BBD confirmation

Hematoxylin and eosin breast tissue slides from archived benign breast biopsy specimen were independently reviewed by study pathologists in a blinded manner (34,35). As previously described (31), a detailed work sheet was completed and BBD subtype was classified as non-proliferative, proliferative without atypia, and atypical hyperplasia (36).

Immunohistochemistry staining for stem cell markers

Details of the tissue microarray (TMA) construction and analyses of immunohistochemistry (IHC)-stained slides have been previously described (31,37,38). Briefly, TMAs were constructed at the Dana Farber/Harvard Cancer Center (DF/HCC) Tissue Microarray Core Facility by obtaining up to three 0.6-mm cores from histopathologically normal terminal duct lobular units (TDLUs) in the archived formalin-fixed paraffin-embedded benign breast biopsy blocks. Normal TDLUs were regions of normal tissue that may or may not be adjacent to benign lesions (31). We previously evaluated our TMA construction methods and confirmed a high success rate (76%) of capturing normal TDLUs in these TMA blocks (39). For each IHC stain, a 5-μm paraffin section was cut from each TMA block and then stained with its commercial antibody (CD44 [DAKO] 1:25 dilution; CD24 [Invitrogen] 1:200 dilution; ALDH1A1 [Abcam] 1:300 dilution) after deparaffinization and rehydration. IHC staining was performed on DAKO AutostainerPlus at the University of Florida Pathology Core Lab according to the previously standardized protocol (37). Appropriate positive and negative controls were included in all staining runs. IHC results were quantified using an automated image analysis system (Definiens Tissue Studio®, Munich, Germany) which quantifies tissue marker expression within the context of tissue architecture. The TMA blocks were sectioned at the same time, and, for each stem cell marker, the TMA sections were stained in one assay run (batch), as well as then analyzed with Definiens in one batch. Because we were interested in investigating molecular changes in breast tissue that occur during the early stages of breast carcinogenesis, the current study focused on stem cell marker expressions in normal TDLUs. The Definiens algorithm segmented each tissue core into epithelium, stroma, and fat, detected the number of cells, and quantified the staining intensity for each marker. For each marker, IHC results were quantified in the percentage of stain-positive cells (across all intensities) in normal epithelial and stromal tissue. To ensure enough cells to estimate the percentage of stain-positive cells, we included staining results with at least 50 cells across the study participant’s TMA cores. Due to differences in the number of available IHC staining results, each marker had a different number of participants included in the analysis (CD44: n=374 for epithelial and 399 stromal; CD24: n=387 for epithelial and 409 stromal; ALDH1A1: n=371 for epithelial and 386 stromal).

Statistical analyses

Percentages of stain-positive cells were log-transformed to improve normality of the residuals. We performed multivariable linear regression to estimate beta coefficients (ß) and 95% confidence intervals (CI) for the associations between anthropometric measures and log-transformed stem cell marker expression in normal epithelium, stroma, and combined epithelium and stroma, adjusting for potential confounders. Multivariable models included age at benign breast biopsy (years), BBD subtype (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia), BBD diagnosis year (1950-1969, 1970-1979, 1980-1989, 1990-1998), menopausal status/hormone therapy use (premenopausal, postmenopausal not using hormone therapy, postmenopausal currently using hormone therapy, other), family history of breast cancer (absent, present), parity/age at first birth (nulliparous, parous/<25 year, parous/25-29 years, parous/≥30 years), breastfeeding history (nulliparous/<1 month, 1-6 months, 7-12 months, ≥13 months), and age at menarche (<12, 12, 13, ≥14 years). Additional adjustment for alcohol intake, smoking, and physical activity did not change the results and thus these variables were not included in the final models. For change in BMI since age 18, multivariable models additionally adjusted for BMI at age 18. We also compared the models with and without mutual adjustment for early-life and adult anthropometric measures. For example, for BMI at age 18, we additionally adjusted for birthweight, height, and weight change since age 18. To reduce collinearity, we adjusted for weight change since age 18 instead of current adult BMI. For current BMI, we additionally adjusted for birthweight, height, and childhood body fatness. For all analyses, we used covariate information that was reported prior to the time of benign breast biopsy, closest to the biopsy date. We performed tests for linear trend using Wald test for category-specific median values. We additionally stratified the analyses by potential effect modifiers: menopausal status, age at benign breast biopsy, presence of family history of breast cancer, and BBD diagnosis year. Finally, we also performed logistic regression models using binary outcomes (above vs. below 10% positivity cut-point) in sensitivity analyses. All analyses were conducted with SAS software 9.3 (SAS Institute Inc., Cary, NC).

Data Availability

The datasets generated and/or analyzed during the current study are available in the Nurses’ Health Study repository after reasonable request.

RESULTS

Study population

The mean age was 45.3 years (range: 17-67 years) and 69.1% of participants were premenopausal at benign breast biopsy. Mean percentages of stain-positive cells for CD44, CD24, and ALDH1A1 were 39.4%, 29.1%, and 26.6%, respectively, in epithelium and 18.1%, 8.7%, and 11.8%, respectively, in stroma. Women with higher BMI at age 18 (≥23.0 vs. <19.0 kg/m2) were more likely to have higher childhood body fatness, lower height, higher current adult BMI, younger age at menarche, non-proliferative breast lesions, and family history of breast cancer (Table 1).

Table 1.

Age and age-adjusted distributions of participant characteristics according to BMI at age 18 years

BMI at age 18 years, kg/m2
<19.0 19.0-19.9 20.0-20.9 21.0-22.9 ≥23.0
N 83 76 65 85 72
Age at benign biopsy a, years 45.5 (7.9) 44 (9.5) 44.2 (10.2) 47 (10.5) 44.7 (8.3)
Adult height, inch 65.4 (2.6) 64.8 (2.3) 64.9 (1.7) 64.2 (2.4) 64.0 (2.2)
Current adult BMI b, kg/m2 21.7 (2.4) 22.2 (2.2) 22.9 (2.6) 25.1 (3.2) 28.4 (5.1)
Change in BMI since age 18 b, kg/m2 3.7 (2.5) 2.7 (2.2) 2.4 (2.6) 3.3 (3.2) 2.5 (4.0)
Birthweight
  <5.5 lbs, % 2.2 4.0 3.6 8.1 8.6
  5.5-6.9 lbs, % 28.5 23.4 27.5 20.9 15.8
  7.0-8.4 lbs, % 25.2 32.1 32.6 35.2 46.5
  8.5-9.9 lbs, % 8.4 10.7 10.0 7.4 6.2
  ≥10.0 lbs, % 2.4 0.0 0.0 2.8 4.0
  Missing, % 33.3 29.8 26.3 25.6 18.9
Average body size at age 5-10 years
  Level 1, % 53.5 41.3 20.4 22.3 6.6
  Level 1.5-2, % 24.8 28.2 35.7 22.9 28.3
  Level 2.5-3, % 8.0 7.5 21.0 10.1 19.6
  Level 3.5-4, % 5.1 9.8 9.1 20.3 13.6
  Level ≥4.5, % 0.0 3.2 10.3 9.6 21.0
  Missing, % 8.6 10.0 3.5 14.8 10.9
Age at menarche
  <12 years, % 18.7 16.3 23.8 32.8 35.0
  12 years, % 26.1 21.6 21.4 26.1 25.6
  13 years, % 26.4 31.1 35.9 25.3 24.5
  ≥14 years, % 28.8 31.0 19.0 15.8 14.9
BBD subtype b
  Nonproliferative, % 20.3 12.2 40.7 34.9 45.7
  Proliferative without atypia, % 54.8 67.7 42.9 57.2 35.5
  Proliferative with atypical hyperplasia, % 24.9 20.0 16.3 7.9 18.8
Calendar year of BBD diagnosis b
  1950-1969, % 0.6 6.0 7.5 1.7 5.5
  1970-1979, % 30.0 25.3 37.0 37.4 28.5
  1980-1989, % 59.2 51.2 39.2 56.7 50.0
  1990-1998, % 10.1 17.6 16.4 4.2 16.0
Family history of breast cancer b, % 10.3 12.2 12.9 15.6 14.5
Menopausal status/HT use b
  Premenopausal, % 74.7 72.1 66.3 71.7 83.5
  Postmenopausal/non-HT users, % 13.5 12.7 23.5 20.8 10.0
  Postmenopausal/current HT users, % 5.2 8.3 4.3 5.8 2.4
  Other, % 6.5 6.9 5.9 1.7 4.1
Parous/age at first birth b
  Nulliparous, % 7.7 8.2 6.9 4.0 10.4
  Parous/<25 years, % 45.1 63.5 51.1 54.4 44.7
  Parous/25-29 years, % 37.3 26.8 25.4 38.4 30.7
  Parous/≥30 years, % 9.9 1.5 16.6 3.1 14.2
Total breastfeeding (among parous women) b
  <1 month, % 42.8 49.8 41.5 54.1 58.0
  1-6 months, % 24.9 16.7 25.6 13.0 12.1
  7-12 months, % 14.7 9.1 18.7 10.9 8.8
  ≥13 months, % 17.6 24.3 14.2 22.0 21.1
Mean percentage of CD44-stain positive cells
  In epithelium 41.8 (33.3) 37.6 (35.2) 31.6 (28.8) 41.3 (34.1) 41.8 (33.6)
  In stroma 18.2 (25) 17.6 (26) 13.5 (20.6) 16.7 (23.6) 18.3 (24.7)
Mean percentage of CD24-stain positive cells
  In epithelium 35 (21.7) 29.5 (21) 27 (22.2) 25.5 (22.9) 27.5 (20.8)
  In stroma 9.4 (11.6) 9.5 (11.4) 10.1 (16.7) 7.7 (13.4) 10.2 (16.4)
Mean percentage of ALDH1A1-stain positive cells
  In epithelium 29.6 (19.6) 26.1 (17.8) 25.8 (19.5) 25 (18.8) 24.8 (15.4)
  In stroma 15.1 (16.4) 12.8 (13.6) 10.5 (9.3) 9.8 (11.8) 7.5 (7.1)
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Values are means (SD) for continuous variables; percentages for categorical variables; and are standardized to the age distribution of the study population.

Values of polytomous variables may not sum to 100% due to rounding

a

Value is not age adjusted

b

At the time of benign breast biopsy

Abbreviations: BBD=benign breast disease, BMI=body mass index; HT=hormone therapy

CD44 expression

Table 2 presents the associations of early-life and adult anthropometric measures with CD44 stem cell marker expression. Greater birthweight was associated with higher expression levels of CD44 in stroma (≥10.0 vs. <5.5 lbs: β [95% CI]=4.29 [1.02, 7.56]; p-trend=0.001). BMI at age 18 years was also positively associated with CD44 expression levels in epithelium (21.0-22.9 vs. <19.0 kg/m2: β [95% CI]=0.75 [0.08, 1.41]; p-trend=0.04). Taller women had higher expression levels of CD44 in epithelium and stroma combined (≥67.0 vs. <63.0 inch: β [95% CI]=0.86 [0.14, 1.58]; p-trend=0.02). The positive associations persisted after mutual adjustment for other anthropometric measures. Childhood body fatness, current BMI, and change in BMI since age 18 were not associated with CD44 expression.

Table 2.

Associations of early-life and adult anthropometric measures with log-transformed CD44 expression levels in histopathologically normal epithelial and stromal tissue from benign breast biopsies

In Epithelium In Stroma In epithelium and stroma combined
N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)		 N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)		 N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)
Birthweight, lbs
  <5.5 21 0 (Ref) 0 (Ref) 24 0 (Ref) 0 (Ref) 24 0 (Ref) 0 (Ref)
  5.5-6.9 83 0.35 (−0.86, 1.55) 0.02 (−1.18, 1.21) 86 2.38 (0.31, 4.46) 2.20 (0.09, 4.32) 87 1.27 (0.11, 2.43) 1.01 (−0.17, 2.19)
  7.0-8.4 119 0.32 (−0.85, 1.48) −0.10 (−1.26, 1.06) 127 2.98 (0.99, 4.98) 2.79 (0.75, 4.83) 127 1.26 (0.15, 2.38) 0.95 (−0.19, 2.09)
  8.5-9.9 31 0.48 (−0.88, 1.84) −0.10 (−1.48, 1.29) 33 3.81 (1.43, 6.20) 3.49 (1.02, 5.97) 33 1.63 (0.30, 2.96) 1.15 (−0.23, 2.53)
  ≥10.0 10 0.60 (−1.23, 2.42) −0.31 (−2.16, 1.55) 10 4.29 (1.02, 7.56) 3.87 (0.46, 7.27) 10 1.80 (−0.03, 3.62) 1.09 (−0.80, 2.98)
  p-trendc 264 0.54 0.67 280 0.001 0.006 281 0.05 0.28
Childhood body fatness (average at age 5-10 years)
  Level 1 117 0 (Ref) 0 (Ref) 125 0 (Ref) 0 (Ref) 125 0 (Ref) 0 (Ref)
  Level 1.5-2 100 0.15 (−0.45, 0.75) 0.16 (−0.45, 0.77) 106 −0.36 (−1.52, 0.79) −0.55 (−1.73, 0.63) 107 −0.18 (−0.80, 0.45) −0.23 (−0.86, 0.40)
  Level 2.5-3 44 0.25 (−0.54, 1.03) 0.12 (−0.68, 0.92) 47 −1.44 (−2.95, 0.07) −1.88 (−3.42, −0.34) 47 −0.11 (−0.92, 0.71) −0.30 (−1.12, 0.53)
  Level 3.5-4 39 0.77 (−0.06, 1.61) 0.68 (−0.16, 1.53) 42 0.61 (−1.00, 2.22) 0.23 (−1.40, 1.87) 42 0.33 (−0.53, 1.20) 0.18 (−0.70, 1.06)
  Level ≥4.5 28 0.05 (−0.90, 1.00) 0.05 (−0.92, 1.03) 30 0.54 (−1.28, 2.36) 0.10 (−1.77, 1.96) 30 −0.15 (−1.13, 0.83) −0.27 (−1.27, 0.74)
  p-trendc 328 0.29 0.39 350 0.67 0.87 351 0.83 0.86
BMI at age 18 years, kg/m2
  <19.0 77 0 (Ref) 0 (Ref) 81 0 (Ref) 0 (Ref) 81 0 (Ref) 0 (Ref)
  19.0-19.9 68 0.01 (−0.67, 0.69) 0.06 (−0.62, 0.75) 76 −0.41 (−1.78, 0.96) −0.43 (−1.81, 0.94) 76 0.001 (−0.76, 0.76) 0.04 (−0.72, 0.80)
  20.0-20.9 56 0.18 (−0.56, 0.91) 0.16 (−0.60, 0.92) 61 −0.04 (−1.52, 1.45) −0.17 (−1.70, 1.35) 62 −0.06 (−0.88, 0.76) −0.10 (−0.94, 0.74)
  21.0-22.9 79 0.75 (0.08, 1.41) 0.82 (0.13, 1.51) 82 1.51 (0.14, 2.89) 1.65 (0.24, 3.07) 82 0.66 (−0.10, 1.42) 0.80 (0.02, 1.58)
  ≥23.0 63 0.50 (−0.20, 1.20) 0.58 (−0.15, 1.32) 68 0.48 (−0.94, 1.89) 0.55 (−0.93, 2.04) 68 0.27 (−0.51, 1.05) 0.42 (−0.40, 1.24)
  p-trendc 343 0.04 0.03 368 0.12 0.12 369 0.22 0.13
Current BMI, kg/m2
  <21.0 80 0 (Ref) 0 (Ref) 87 0 (Ref) 0 (Ref) 87 0 (Ref) 0 (Ref)
  21.0-22.9 101 0.16 (−0.46, 0.79) 0.17 (−0.47, 0.81) 108 0.11 (−1.14, 1.36) −0.06 (−1.32, 1.20) 108 −0.08 (−0.77, 0.62) −0.10 (−0.80, 0.60)
  23.0-24.9 73 0.07 (−0.60, 0.75) 0.12 (−0.57, 0.81) 78 −0.11 (−1.48, 1.26) −0.14 (−1.52, 1.24) 79 0.01 (−0.75, 0.77) 0.05 (−0.72, 0.81)
  25.0-29.9 66 0.43 (−0.27, 1.14) 0.47 (−0.25, 1.18) 70 0.04 (−1.37, 1.46) −0.005 (−1.43, 1.42) 70 0.01 (−0.77, 0.80) 0.07 (−0.72, 0.87)
  ≥30.0 30 0.13 (−0.78, 1.05) 0.20 (−0.74, 1.14) 32 0.02 (−1.80, 1.85) −0.27 (−2.13, 1.59) 32 −0.28 (−1.29, 0.73) −0.23 (−1.27, 0.81)
  p-trendc 350 0.50 0.42 375 0.98 0.83 376 0.73 0.89
Change in BMI since age 18, kg/m2
  ≤0 53 0 (Ref) 0 (Ref) 59 0 (Ref) 0 (Ref) 59 0 (Ref) 0 (Ref)
  0.1-2.0 85 −0.25 (−0.98, 0.48) −0.21 (−0.96, 0.55) 90 0.54 (−0.92, 2.00) 0.40 (−1.09, 1.88) 90 0.03 (−0.77, 0.84) 0.05 (−0.78, 0.87)
  2.1-4.0 78 −0.09 (−0.85, 0.66) −0.05 (−0.84, 0.73) 84 0.80 (−0.70, 2.31) 0.61 (−0.93, 2.16) 85 0.15 (−0.68, 0.98) 0.12 (−0.74, 0.97)
  4.1-7.0 79 0.01 (−0.75, 0.77) 0.04 (−0.74, 0.82) 83 −0.06 (−1.58, 1.46) −0.23 (−1.77, 1.31) 83 0.13 (−0.71, 0.97) 0.12 (−0.74, 0.97)
  >7.0 35 −0.30 (−1.22, 0.63) −0.22 (−1.17, 0.73) 39 −0.48 (−2.30, 1.34) −0.55 (−2.39, 1.29) 39 −0.80 (−1.80, 0.21) −0.69 (−1.71, 0.34)
  p-trendc 330 0.89 0.98 355 0.35 0.31 356 0.24 0.31
Adult height, inch
  <63.0 77 0 (Ref) 0 (Ref) 83 0 (Ref) 0 (Ref) 83 0 (Ref) 0 (Ref)
  63.0-64.9 119 0.41 (−0.23, 1.06) 0.48 (−0.18, 1.13) 128 0.64 (−0.57, 1.86) 0.60 (−0.62, 1.83) 128 0.59 (−0.07, 1.25) 0.59 (−0.08, 1.26)
  65.0-65.9 45 0.35 (−0.47, 1.18) 0.48 (−0.36, 1.31) 48 0.27 (−1.30, 1.84) 0.20 (−1.39, 1.79) 48 0.34 (−0.51, 1.19) 0.34 (−0.52, 1.21)
  66.0-66.9 49 0.68 (−0.13, 1.48) 0.78 (−0.04, 1.60) 50 0.80 (−0.75, 2.35) 0.64 (−0.94, 2.21) 51 1.02 (0.18, 1.86) 1.01 (0.15, 1.86)
  ≥67.0 84 0.48 (−0.22, 1.18) 0.56 (−0.17, 1.29) 90 0.83 (−0.50, 2.16) 0.54 (−0.83, 1.91) 90 0.86 (0.14, 1.58) 0.82 (0.06, 1.57)
  p-trendc 374 0.18 0.13 399 0.26 0.52 400 0.02 0.03
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a

Model 1 included age at biopsy (years, continuous), BBD type (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia), BBD year (1950-1969, 1970-1979, 1980-1989, 1990-1998), menopausal status (premenopausal, postmenopausal/non-HT users, postmenopausal/current HT users, others), family history of breast cancer (present, absent), parity/age at first birth (nulliparous, parous/<25 year, parous/25-29 years, parous/≥30 years), breastfeeding history (nulliparous/<1 month, 1-6 months, 7-12 months, ≥13 months), age at menarche (<12, 12, 13, ≥14 years), and, for change in BMI since age 18 exposure, BMI at age 18 (kg/m2, continuous). Beta coefficients and 95% confidence intervals are in log scale.

b

Model 2 additionally included mutual adjustment for early-life and adult anthropometric measures (for birthweight exposure: included childhood body fatness, current BMI, and adult height; for childhood body fatness exposure: included birthweight, current BMI, and adult height; for BMI at age 18 exposure: included birthweight, change in BMI since age 18, and adult height; for current BMI and change in BMI since age 18 exposures: included birthweight, childhood body fatness, and adult height; for height: birthweight, childhood body fatness, and current BMI). Beta coefficients and 95% confidence intervals are in log scale.

c

p-trend was estimated using the Wald test for category-specific median values

CD24 expression

Table 3 presents the associations of early-life and adult anthropometric measures with CD24 expression. Childhood body fatness was inversely (Level 3.5-4 vs. 1: β [95% CI]= −0.64 [−1.12, −0.15]; p-trend=0.03) and height was suggestively positively (≥67.0 vs. <63.0 inch: β [95% CI]=0.37 [−0.06, 0.80]; p-trend=0.03) associated with combined CD24 expression levels in stroma and epithelium. Birthweight, current BMI, and change in BMI since age 18 were not associated with CD24 expression. The associations were similar after mutual adjustment for other anthropometric measures.

Table 3.

Associations of early-life and adult anthropometric measures with log-transformed CD24 expression levels in histopathologically normal epithelial and stromal tissue from benign breast biopsies

In epithelium In stroma In epithelium and stroma combined
N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)		 N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)		 N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)
Birthweight, lbs
  <5.5 22 0 (Ref) 0 (Ref) 24 0 (Ref) 0 (Ref) 24 0 (Ref) 0 (Ref)
  5.5-6.9 83 0.37 (−0.27, 1.00) 0.38 (−0.27, 1.04) 88 0.98 (−0.41, 2.37) 0.97 (−0.45, 2.38) 89 0.54 (−0.11, 1.20) 0.49 (−0.17, 1.16)
  7.0-8.4 125 0.41 (−0.20, 1.02) 0.47 (−0.16, 1.11) 132 0.80 (−0.54, 2.13) 0.87 (−0.50, 2.23) 133 0.31 (−0.32, 0.94) 0.29 (−0.36, 0.93)
  8.5-9.9 36 0.37 (−0.33, 1.07) 0.43 (−0.32, 1.17) 37 1.10 (−0.47, 2.66) 1.03 (−0.60, 2.66) 37 0.59 (−0.14, 1.33) 0.47 (−0.30, 1.24)
  ≥10.0 10 0.56 (−0.42, 1.54) 0.69 (−0.34, 1.73) 10 1.09 (−1.12, 3.29) 1.18 (−1.12, 3.48) 10 0.57 (−0.47, 1.61) 0.45 (−0.63, 1.54)
  p-trendc 276 0.33 0.23 291 0.40 0.40 293 0.48 0.71
Childhood body fatness (average at age 5-10 years)
  Level 1 120 0 (Ref) 0 (Ref) 126 0 (Ref) 0 (Ref) 127 0 (Ref) 0 (Ref)
  Level 1.5-2 106 0.14 (−0.24, 0.52) 0.17 (−0.22, 0.56) 111 0.47 (−0.30, 1.25) 0.49 (−0.31, 1.29) 111 0.11 (−0.23, 0.46) 0.14 (−0.21, 0.50)
  Level 2.5-3 48 0.05 (−0.45, 0.54) 0.03 (−0.48, 0.54) 50 −0.18 (−1.19, 0.82) −0.19 (−1.23, 0.85) 52 0.05 (−0.40, 0.49) 0.07 (−0.39, 0.52)
  Level 3.5-4 39 −0.11 (−0.66, 0.43) −0.10 (−0.65, 0.46) 43 −0.49 (−1.57, 0.60) −0.46 (−1.58, 0.65) 43 −0.64 (−1.12, −0.15) −0.58 (−1.08, −0.09)
  Level ≥4.5 28 −0.28 (−0.90, 0.33) −0.29 (−0.93, 0.34) 29 −0.03 (−1.29, 1.23) −0.06 (−1.36, 1.25) 29 −0.38 (−0.94, 0.19) −0.36 (−0.94, 0.22)
  p-trendc 341 0.38 0.36 359 0.45 0.44 362 0.03 0.04
BMI at age 18 years, kg/m2
  <19.0 81 0 (Ref) 0 (Ref) 83 0 (Ref) 0 (Ref) 83 0 (Ref) 0 (Ref)
  19.0-19.9 72 −0.16 (−0.60, 0.28) −0.19 (−0.64, 0.26) 75 −0.03 (−0.99, 0.93) −0.09 (−1.06, 0.88) 76 −0.09 (−0.55, 0.37) −0.08 (−0.55, 0.39)
  20.0-20.9 58 −0.93 (−1.42, −0.45) −0.92 (−1.43, −0.41) 63 −0.75 (−1.79, 0.29) −0.93 (−2.00, 0.15) 64 −0.46 (−0.96, 0.04) −0.51 (−1.02, 0.01)
  21.0-22.9 77 −0.35 (−0.79, 0.09) −0.43 (−0.89, 0.03) 84 −0.87 (−1.83, 0.09) −1.10 (−2.09, −0.10) 84 −0.60 (−1.06, −0.14) −0.63 (−1.11, −0.15)
  ≥23.0 66 −0.39 (−0.85, 0.07) −0.49 (−0.98, −0.01) 71 −0.55 (−1.54, 0.43) −0.91 (−1.95, 0.13) 72 −0.30 (−0.78, 0.17) −0.38 (−0.88, 0.13)
  p-trendc 354 0.13 0.06 376 0.14 0.04 379 0.09 0.06
Current BMI, kg/m2
  <21.0 84 0 (Ref) 0 (Ref) 90 0 (Ref) 0 (Ref) 90 0 (Ref) 0 (Ref)
  21.0-22.9 106 −0.28 (−0.63, 0.07) −0.32 (−0.68, 0.04) 110 −0.85 (−1.70, 0.01) −0.88 (−1.75, −0.01) 110 −0.39 (−0.80, 0.02) −0.37 (−0.79, 0.04)
  23.0-24.9 78 −0.33 (−0.72, 0.06) −0.35 (−0.74, 0.04) 80 −0.80 (−1.74, 0.13) −0.83 (−1.79, 0.13) 83 −0.16 (−0.61, 0.29) −0.13 (−0.58, 0.32)
  25.0-29.9 63 −0.28 (−0.69, 0.13) −0.32 (−0.73, 0.10) 71 −1.14 (−2.11, −0.18) −1.12 (−2.11, −0.13) 71 −0.67 (−1.14, −0.20) −0.59 (−1.07, −0.12)
  ≥30.0 32 −0.22 (−0.74, 0.29) −0.22 (−0.75, 0.31) 34 −0.98 (−2.21, 0.24) −1.01 (−2.28, 0.26) 34 −0.28 (−0.88, 0.31) −0.16 (−0.77, 0.45)
  p-trendc 363 0.43 0.45 385 0.08 0.10 388 0.13 0.33
Change in BMI since age 18, kg/m2
  ≤0 57 0 (Ref) 0 (Ref) 61 0 (Ref) 0 (Ref) 62 0 (Ref) 0 (Ref)
  0.1-2.0 86 −0.18 (−0.60, 0.24) −0.24 (−0.67, 0.20) 92 −0.85 (−1.86, 0.16) −0.98 (−2.02, 0.05) 92 −0.37 (−0.85, 0.12) −0.43 (−0.93, 0.06)
  2.1-4.0 85 −0.18 (−0.61, 0.25) −0.26 (−0.70, 0.19) 87 −0.39 (−1.43, 0.65) −0.59 (−1.67, 0.48) 88 −0.11 (−0.61, 0.39) −0.24 (−0.75, 0.27)
  4.1-7.0 78 −0.11 (−0.55, 0.33) −0.17 (−0.63, 0.28) 82 −0.87 (−1.93, 0.19) −0.99 (−2.07, 0.10) 83 −0.28 (−0.79, 0.23) −0.35 (−0.87, 0.17)
  >7.0 35 −0.02 (−0.56, 0.52) −0.09 (−0.63, 0.46) 41 −1.02 (−2.28, 0.23) −1.15 (−2.43, 0.14) 41 −0.49 (−1.09, 0.12) −0.55 (−1.16, 0.07)
  p-trendc 341 0.94 0.89 363 0.13 0.11 366 0.21 0.16
Adult height, inch
  <63.0 78 0 (Ref) 0 (Ref) 88 0 (Ref) 0 (Ref) 88 0 (Ref) 0 (Ref)
  63.0-64.9 122 −0.24 (−0.63, 0.15) −0.24 (−0.64, 0.16) 130 −0.12 (−0.93, 0.69) −0.18 (−1.00, 0.64) 131 −0.04 (−0.43, 0.35) −0.05 (−0.45, 0.34)
  65.0-65.9 45 −0.02 (−0.52, 0.48) −0.03 (−0.55, 0.48) 48 0.11 (−0.94, 1.17) −0.01 (−1.09, 1.07) 48 0.22 (−0.29, 0.73) 0.20 (−0.32, 0.72)
  66.0-66.9 51 −0.05 (−0.54, 0.43) −0.06 (−0.56, 0.44) 52 −0.09 (−1.12, 0.94) −0.21 (−1.26, 0.84) 53 0.35 (−0.15, 0.84) 0.31 (−0.19, 0.81)
  ≥67.0 91 −0.02 (−0.44, 0.40) −0.06 (−0.50, 0.38) 91 0.36 (−0.53, 1.25) 0.23 (−0.69, 1.15) 92 0.37 (−0.06, 0.80) 0.33 (−0.11, 0.77)
  p-trendc 387 0.76 0.91 409 0.38 0.58 412 0.03 0.05
Open in a new tab
a

Model 1 included age at biopsy (years, continuous), BBD type (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia), BBD year (1950-1969, 1970-1979, 1980-1989, 1990-1998), menopausal status (premenopausal, postmenopausal/non-HT users, postmenopausal/current HT users, others), family history of breast cancer (present, absent), parity/age at first birth (nulliparous, parous/<25 year, parous/25-29 years, parous/≥30 years), breastfeeding history (nulliparous/<1 month, 1-6 months, 7-12 months, ≥13 months), age at menarche (<12, 12, 13, ≥14 years), and, for change in BMI since age 18 exposure, BMI at age 18 (kg/m2, continuous). Beta coefficients and 95% confidence intervals are in log scale.

b

Model 2 additionally included mutual adjustment for early-life and adult anthropometric measures (for birthweight exposure: included childhood body fatness, current BMI, and adult height; for childhood body fatness exposure: included birthweight, current BMI, and adult height; for BMI at age 18 exposure: included birthweight, change in BMI since age 18, and adult height; for current BMI and change in BMI since age 18 exposures: included birthweight, childhood body fatness, and adult height; for height: birthweight, childhood body fatness, and current BMI). Beta coefficients and 95% confidence intervals are in log scale.

c

p-trend was estimated using the Wald test for category-specific median values

ALDH1A1 expression

Table 4 presents the associations of early-life and adult anthropometric measures with ALDH1A1 expression. Anthropometric measures were not associated with ALDH1A1 expression.

Table 4.

Associations of early-life and adult anthropometric measures with log-transformed ALDH1A1 expression levels in histopathologically normal epithelial and stromal tissue from benign breast biopsies

In epithelium In stroma In epithelium and stroma combined
N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)		 N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)		 N MV model a
β (95% CI)		 MV + mutual
adjustment b
β (95% CI)
Birthweight, lbs
  <5.5 22 0 (Ref) 0 (Ref) 22 0 (Ref) 0 (Ref) 24 0 (Ref) 0 (Ref)
  5.5-6.9 81 −0.005 (−0.50, 0.49) −0.12 (−0.63, 0.38) 85 −0.16 (−1.41, 1.10) −0.27 (−1.54, 1.00) 88 0.15 (−0.27, 0.56) 0.07 (−0.35, 0.49)
  7.0-8.4 120 0.05 (−0.44, 0.53) −0.13 (−0.62, 0.36) 125 0.18 (−1.02, 1.39) −0.03 (−1.25, 1.20) 129 0.17 (−0.23, 0.57) 0.06 (−0.35, 0.47)
  8.5-9.9 31 0.03 (−0.53, 0.59) −0.14 (−0.73, 0.45) 35 −0.31 (−1.72, 1.09) −0.41 (−1.86, 1.04) 35 0.16 (−0.32, 0.63) 0.08 (−0.41, 0.57)
  ≥10.0 10 0.29 (−0.47, 1.04) −0.001 (−0.79, 0.79) 9 −0.52 (−2.51, 1.48) −0.79 (−2.86, 1.28) 10 0.38 (−0.28, 1.04) 0.19 (−0.49, 0.88)
  p-trendc 264 0.51 0.89 276 0.81 0.65 286 0.36 0.71
Childhood body fatness (average at age 5-10 years)
  Level 1 117 0 (Ref) 0 (Ref) 119 0 (Ref) 0 (Ref) 126 0 (Ref) 0 (Ref)
  Level 1.5-2 98 0.02 (−0.24, 0.29) 0.02 (−0.24, 0.29) 105 −0.24 (−0.84, 0.36) −0.26 (−0.87, 0.36) 108 −0.02 (−0.24, 0.21) −0.01 (−0.24, 0.22)
  Level 2.5-3 47 0.14 (−0.19, 0.48) 0.13 (−0.21, 0.47) 46 0.18 (−0.62, 0.97) 0.09 (−0.72, 0.90) 49 0.12 (−0.17, 0.41) 0.12 (−0.18, 0.41)
  Level 3.5-4 38 −0.09 (−0.45, 0.28) −0.08 (−0.45, 0.29) 41 −0.91 (−1.76, −0.07) −0.97 (−1.82, −0.11) 43 −0.11 (−0.42, 0.21) −0.09 (−0.41, 0.23)
  Level ≥4.5 28 0.42 (0.01, 0.83) 0.36 (−0.06, 0.78) 28 0.21 (−0.77, 1.19) 0.05 (−0.96, 1.06) 29 0.29 (−0.07, 0.65) 0.26 (−0.11, 0.63)
  p-trendc 328 0.19 0.28 339 0.58 0.37 355 0.35 0.42
BMI at age 18 years, kg/m2
  <19.0 78 0 (Ref) 0 (Ref) 83 0 (Ref) 0 (Ref) 83 0 (Ref) 0 (Ref)
  19.0-19.9 69 −0.24 (−0.56, 0.08) −0.25 (−0.57, 0.07) 68 −0.16 (−0.93, 0.62) −0.14 (−0.93, 0.65) 75 −0.22 (−0.50, 0.05) −0.22 (−0.50, 0.06)
  20.0-20.9 60 −0.25 (−0.60, 0.09) −0.30 (−0.65, 0.06) 61 0.05 (−0.77, 0.87) −0.01 (−0.86, 0.84) 63 −0.23 (−0.53, 0.06) −0.26 (−0.57, 0.05)
  21.0-22.9 72 −0.08 (−0.40, 0.24) −0.07 (−0.40, 0.26) 78 −0.05 (−0.82, 0.72) −0.02 (−0.82, 0.77) 82 −0.13 (−0.41, 0.14) −0.12 (−0.41, 0.17)
  ≥23.0 63 0.005 (−0.33, 0.34) 0.07 (−0.27, 0.42) 65 −0.34 (−1.14, 0.45) −0.22 (−1.06, 0.62) 69 −0.15 (−0.43, 0.14) −0.10 (−0.41, 0.20)
  p-trendc 342 0.61 0.37 355 0.45 0.69 372 0.55 0.80
Current BMI, kg/m2
  <21.0 80 0 (Ref) 0 (Ref) 84 0 (Ref) 0 (Ref) 90 0 (Ref) 0 (Ref)
  21.0-22.9 102 −0.08 (−0.37, 0.21) −0.09 (−0.39, 0.20) 105 0.47 (−0.22, 1.15) 0.48 (−0.21, 1.17) 109 −0.08 (−0.32, 0.17) −0.08 (−0.33, 0.17)
  23.0-24.9 75 −0.10 (−0.41, 0.22) −0.04 (−0.36, 0.28) 74 −0.38 (−1.14, 0.38) −0.29 (−1.07, 0.48) 79 −0.17 (−0.44, 0.11) −0.12 (−0.39, 0.16)
  25.0-29.9 63 0.08 (−0.25, 0.41) 0.09 (−0.25, 0.42) 69 0.47 (−0.30, 1.24) 0.52 (−0.26, 1.30) 69 0.001 (−0.28, 0.28) 0.02 (−0.26, 0.31)
  ≥30.0 29 0.14 (−0.29, 0.58) 0.13 (−0.32, 0.57) 30 0.29 (−0.72, 1.30) 0.27 (−0.77, 1.31) 32 −0.0001 (−0.37, 0.37) 0.005 (−0.37, 0.38)
  p-trendc 349 0.30 0.30 362 0.57 0.57 379 0.81 0.73
Change in BMI since age 18, kg/m2
  ≤0 54 0 (Ref) 0 (Ref) 53 0 (Ref) 0 (Ref) 61 0 (Ref) 0 (Ref)
  0.1-2.0 86 0.11 (−0.23, 0.45) 0.11 (−0.24, 0.45) 89 0.53 (−0.30, 1.36) 0.62 (−0.23, 1.47) 92 0.11 (−0.18, 0.40) 0.12 (−0.18, 0.41)
  2.1-4.0 78 0.06 (−0.30, 0.42) 0.08 (−0.29, 0.44) 83 0.30 (−0.56, 1.17) 0.41 (−0.48, 1.29) 84 0.05 (−0.26, 0.35) 0.05 (−0.26, 0.36)
  4.1-7.0 78 0.02 (−0.33, 0.38) 0.07 (−0.30, 0.43) 79 0.29 (−0.59, 1.17) 0.36 (−0.54, 1.25) 82 −0.02 (−0.32, 0.29) 0.01 (−0.30, 0.32)
  >7.0 34 0.18 (−0.26, 0.61) 0.19 (−0.25, 0.63) 38 0.61 (−0.42, 1.64) 0.75 (−0.30, 1.79) 40 0.08 (−0.29, 0.44) 0.12 (−0.24, 0.49)
  p-trendc 330 0.69 0.54 342 0.48 0.38 359 0.91 0.85
Adult height, inch
  <63.0 75 0 (Ref) 0 (Ref) 82 0 (Ref) 0 (Ref) 86 0 (Ref) 0 (Ref)
  63.0-64.9 119 0.08 (−0.20, 0.36) 0.06 (−0.22, 0.35) 123 0.43 (−0.21, 1.08) 0.43 (−0.23, 1.09) 128 0.08 (−0.15, 0.32) 0.07 (−0.17, 0.31)
  65.0-65.9 42 0.44 (0.08, 0.80) 0.44 (0.07, 0.81) 46 0.48 (−0.36, 1.31) 0.51 (−0.35, 1.37) 48 0.32 (0.01, 0.62) 0.32 (0.004, 0.63)
  66.0-66.9 49 0.37 (0.02, 0.72) 0.37 (0.01, 0.72) 48 0.73 (−0.10, 1.56) 0.74 (−0.10, 1.59) 50 0.37 (0.07, 0.67) 0.36 (0.05, 0.67)
  ≥67.0 86 0.09 (−0.21, 0.39) 0.09 (−0.22, 0.40) 87 0.10 (−0.60, 0.81) 0.20 (−0.53, 0.94) 91 0.11 (−0.14, 0.37) 0.11 (−0.15, 0.38)
  p-trendc 371 0.34 0.34 386 0.78 0.57 403 0.19 0.20
Open in a new tab
a

Model 1 included age at biopsy (years, continuous), BBD type (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia), BBD year (1950-1969, 1970-1979, 1980-1989, 1990-1998), menopausal status (premenopausal, postmenopausal/non-HT users, postmenopausal/current HT users, others), family history of breast cancer (present, absent), parity/age at first birth (nulliparous, parous/<25 year, parous/25-29 years, parous/≥30 years), breastfeeding history (nulliparous/<1 month, 1-6 months, 7-12 months, ≥13 months), age at menarche (<12, 12, 13, ≥14 years), and, for change in BMI since age 18 exposure, BMI at age 18 (kg/m2, continuous). Beta coefficients and 95% confidence intervals are in log scale.

b

Model 2 additionally included mutual adjustment for early-life and adult anthropometric measures (for birthweight exposure: included childhood body fatness, current BMI, and adult height; for childhood body fatness exposure: included birthweight, current BMI, and adult height; for BMI at age 18 exposure: included birthweight, change in BMI since age 18, and adult height; for current BMI and change in BMI since age 18 exposures: included birthweight, childhood body fatness, and adult height; for height: birthweight, childhood body fatness, and current BMI). Beta coefficients and 95% confidence intervals are in log scale.

c

p-trend was estimated using the Wald test for category-specific median values

Similar patterns of associations were observed when stratifying by menopausal status (Supplementary Table 1), age at benign breast biopsy (Supplementary Table 2), presence of family history of breast cancer (Supplementary Table 3), and calendar year of BBD diagnosis (Supplementary Table 4). Results were also similar when restricting the analyses to controls (Supplementary Table 5) and when logistic regression models were performed using binary cut-points for stem cell marker expression levels (Supplementary Table 6).

DISCUSSION

In this study, birthweight, childhood body fatness, and height were associated with stem cell marker expression levels among women with BBD. Birthweight was positively associated with expression levels of CD44, whereas childhood body fatness was inversely associated with CD24 expression. Height was positively associated with expression levels of CD44 and CD24. Our data suggest that early-life and adult anthropometric measures may be associated with the expression of stem cell population in normal breast tissue from cancer-free women.

Our finding of positive association between birthweight and stem cell marker CD44 expression is consistent with previous findings of percent mammographic density (PMD) (10) and breast cancer risk (1-3). In previous studies, birthweight was positively associated with percent mammographic density (PMD) (10). PMD indicates the relative amount of dense versus nondense tissue in the breast and is a strong risk factor of breast cancer (40). PMD is also thought to reflect the number of mammary tissue-specific stem cells (41), as higher levels of stem cell marker expression were observed in dense tissue compared to non-dense tissue (41). Altogether, these findings are consistent with the stem cell hypothesis that suggests an important role of stem cells in breast carcinogenesis (18,19). Higher birthweight may indicate higher intrauterine exposure to hormones, such as insulin-like growth factor (IGF)-I (42,43), IGF-II (42-45), and estrogen (46,47), that stimulate proliferation in the breast. Intrauterine exposures to proliferative factors may contribute to expansion of stem cell population in the mammary gland, leading to higher mammary gland mass and PMD. Consistent with this hypothesis, a previous study showed that maternal levels of IGF-I and steroid hormones were positively associated with the number of hematopoietic stem cells in umbilical cord blood (48,49). Studies have also shown that higher birthweight was associated with higher circulating levels of adult IGF-I (50), suggesting that the impact of intrauterine exposures on cellular proliferation may be extended to adulthood.

Similarly, we observed positive associations of adult height with expression levels of CD44 and CD24 stem cell markers. Adult height may be influenced by birthweight, genetics, and age of puberty (51). Height also indicates early-life nutritional status and early-life exposure to growth hormones and growth factors, including IGF-I. IGF signaling pathway regulates stem cell maintenance and is involved in a natural process of tissue remodeling during which cells acquire stem cell-like characteristics (52). In the NHS (11), height was positively associated with PMD in premenopausal women, although no association was observed in postmenopausal women. In pooled analyses, taller women had higher circulating levels of adult IGF-I (53) and higher breast cancer risk (5). These findings suggest that early-life exposures to growth factors may play an important role in determining the amount of stem cell population throughout women’s life.

In contrast to the positive associations of birthweight and height, we observed that childhood body fatness was inversely associated with stem cell marker CD24 expression levels. Consistently, studies have shown that childhood body fatness is associated with lower PMD (11,54-60). In our previous study (13), we further investigated breast tissue composition and found an association of childhood body fatness with lower percentage of fibrous stromal tissue on benign breast biopsies. Further, early-life body fatness was also associated with lower image intensity variation of dense tissue on a mammogram (11), suggesting that body fatness may have impact on breast tissue architecture beyond breast density. Studies have also reported lower circulating levels of adult IGF-I (50,61) and lower expression levels of proliferation marker Ki67 in normal breast tissue (14) among women who were overweight or obese during childhood. Altogether, these findings suggest that body fatness may contribute to reduced replication of stem cells and thereby may influence breast tissue remodeling. These findings are also in line with the evidence showing lower breast cancer risk associated with early-life body fatness (7-9), further supporting the notion that stem cell pool size may mediate the early-life body fatness and breast cancer risk association. However, studies are needed to confirm our results and further investigate the role of CD24 in cancer-free women, particularly by using co-localized measures of CD44 and CD24. Previous studies suggest that CD44-high/CD24-low co-localized expression characterizes the breast cancer stem cell phenotype (62,63) but little is known about the role of co-localization of these markers in cancer-free women.

This study is the first to examine the associations of early-life and adult anthropometric measures with multiple stem cell marker expressions in normal breast tissue of cancer-free women. The analysis used data from the Nurses’ Health Study and Nurses’ Health Study II, established cohorts with more than 30 years of follow-up, confirmed benign breast disease status, and comprehensive information on breast cancer risk factors. We also confirmed that all participants were cancer-free at benign breast biopsy. Lastly, the distributions of risk factors were also similar between women with and without biopsy specimen, reducing the likelihood of selection bias.

We also acknowledge several limitations of our study. First, we used self-reported anthropometric data and thus the measurement error cannot be ruled out. However, measurement error is likely to be non-differential in respect to outcomes because we used the anthropometric data that were collected prior to benign breast biopsy. Second, we examined the associations among women with BBD and thus our results may not be generalizable to women without BBD. We cannot exclude the possibility that normal breast tissue on benign biopsies have been influenced by the neighboring benign lesions (e.g., field effect). Third, because we used TMA cores to quantify the IHC-stained stem cell marker expressions, the outcome data may potentially include measurement error if there is heterogeneity in marker expression throughout the breast. However, in our reliability study, we confirmed moderate to high correlations in stem cell marker expressions across TMA cores within a woman (intraclass correlation coefficient=0.71-0.80 CD44; 0.48-0.63 CD24, 0.51-0.58 ALDH1A1) (37). Finally, in our study, we did not measure co-localization of stem cell markers. Some studies from breast tumors (62,63) suggest that CD44-high/CD24-low/ALDH1A1-high cells are associated with cancer malignancy and poor prognosis. Further studies are needed to investigate the associations with co-expression of stem cell markers.

In summary, birthweight, childhood body fatness, and height were associated with stem cell marker expression levels in histopathologically normal breast tissue among women with BBD. These findings contribute to our understanding of breast cancer etiology and suggest that these risk factors may influence breast cancer risk by altering the number and activity of stem cell population in the breast. Further studies are needed to investigate the potential role of stem cell markers as an underlying mechanism for breast cancer development.

Supplementary Material

1
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6

Acknowledgements:

The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming.

Funding information:

This work was supported by the National Cancer Institute at the National Institutes of Health [CA240341 to L.Y., CA131332, CA175080 to R.M.T., P01 CA87969, UM1 CA186107, U01 CA176726 to A.H.E.], Avon Foundation for Women, Susan G. Komen for the Cure®, and Breast Cancer Research Foundation. H.O. was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF) grants (RS-2023-00219289; NRF-2023S1A5C2A03095169).

Footnotes

Ethics approval and consent to participate:

The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Consent was obtained or implied by return of questionnaires. The study was conducted in accordance with the Declaration of Helsinki.

Consent for publication:

Consent for publication was obtained from the study participants.

Competing interests:

The authors declare no conflict of interest.

Data availability:

The datasets generated and/or analysed during the current study are available in the Nurses’ Health Study repository after reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS1990174-supplement-1.docx (22.6KB, docx)
2
NIHMS1990174-supplement-2.docx (21KB, docx)
3
NIHMS1990174-supplement-3.docx (21.1KB, docx)
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NIHMS1990174-supplement-4.docx (20.9KB, docx)
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NIHMS1990174-supplement-5.docx (19.2KB, docx)
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NIHMS1990174-supplement-6.docx (22.6KB, docx)

Data Availability Statement

The datasets generated and/or analyzed during the current study are available in the Nurses’ Health Study repository after reasonable request.

The datasets generated and/or analysed during the current study are available in the Nurses’ Health Study repository after reasonable request.

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