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Epidemiology

Associations of stem cell markers CD44, CD24 and ALDH1A1 with mammographic breast density in women with benign breast biopsies

Abstract

Background

We examined associations of CD44, CD24 and ALDH1A1 breast stem cell markers with mammographic breast density (MBD), a well-established breast cancer (BCa) risk factor.

Methods

We included 218 cancer-free women with biopsy-confirmed benign breast disease within the Nurses’ Health Study (NHS) and NHSII. The data on BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as percent of positively stained cells for each marker out of the total cell count. MBD was assessed with computer-assisted techniques. Generalised linear regression was used to examine the associations of each marker with square root-transformed percent density (PD), absolute dense and non-dense areas (NDA), adjusted for BCa risk factors.

Results

Stromal CD44 and ALDH1A1 expression was positively associated with PD (≥ 10% vs. <10% β = 0.56, 95% confidence interval [CI] [0.06; 1.07] and β = 0.81 [0.27; 1.34], respectively) and inversely associated with NDA (β per 10% increase = −0.17 [−0.34; −0.01] and β for ≥10% vs. <10% = −1.17 [−2.07; −0.28], respectively). Epithelial CD24 expression was inversely associated with PD (β per 10% increase = −0.14 [−0.28; −0.01]. Stromal and epithelial CD24 expression was positively associated with NDA (β per 10% increase = 0.35 [0.2 × 10−2; 0.70] and β per 10% increase = 0.34 [0.11; 0.57], respectively).

Conclusion

Expression of stem cell markers is associated with MBD.

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Fig. 1: Distribution of stem cell marker expression in normal terminal duct-lobular units from benign breast biopsies.

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Data availability

The data that support the findings of this study are available from the Nurses’ Health Studies, however they are not publicly available. Investigators interested in using the data can request access, and feasibility will be discussed at an investigators’ meeting. Limits are not placed on scientific questions or methods, and there is no requirement for co-authorship. Additional data-sharing information and policy details can be accessed at http://www.nurseshealthstudy.org/researchers.

Code availability

The underlying code for this study is not publicly available but may be made available to qualified researchers on reasonable request from the corresponding author.

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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 centres. 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

This work was supported by the National Cancer Institute at the National Institutes of Health [CA240341 to LY, CA131332, CA175080, P01 CA087969 to RMT, UM1 CA186107 and, to MS, U01 CA176726 to WW], Avon Foundation for Women, Susan G. Komen for the Cure®, and Breast Cancer Research Foundation.

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LY and RT conceived of and designed the study, directed statistical analyses, interpreted results, substantially revised initial drafts of the paper and provided final review and approval. LY performed statistical analyses. YH assessed IHC results. LY wrote the first draft of the manuscript which was revised with contribution from YH, GB, DM, MM, BR and RT. LY supervised the overall study progress. All authors read and approved the final manuscript.

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Correspondence to Lusine Yaghjyan.

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This study was performed in accordance with the Declaration of Helsinki. 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, and University of Florida Institutional Review Boards. Consent was obtained or implied by the return of questionnaires.

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Yaghjyan, L., Heng, Y.J., Baker, G.M. et al. Associations of stem cell markers CD44, CD24 and ALDH1A1 with mammographic breast density in women with benign breast biopsies. Br J Cancer 131, 325–333 (2024). https://doi.org/10.1038/s41416-024-02743-2

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