Proteogenomic characterization of invasive breast tumors in young women

Breast cancer in women <40, accounting for ~5% of all breast cancer cases diagnosed in the U.S., is more aggressive and associated with worse outcomes compared to breast cancer in older women. We performed a first-ever integrated proteogenomic study from a matched cohort of laser-microdissected tumors of 34 young (<40 years) and 34 older (≥60 years) women to identify molecular features that may underlie the worse outcomes in young women. Progression-free interval was shorter in young women, and their tumors were enriched for more aggressive molecular subtypes. Our multi-omic analysis identified distinct clusters between age groups in luminal but not basal-like cancers. Notably, GATA3 mutations were enriched in luminal tumors from young women while TP53 and PIK3CA mutations were more common in luminal tumors from older women. Young women's tumors exhibited lower estrogen receptor (ER) expression yet paradoxically enhanced ER response pathways and increased expression of tamoxifen-resistance-associated genes (IRS1, FERMT1). Immune pathway activity and immune scores were lower in tumors from young women, whereas proliferative and MYC pathways were notably elevated, identifying potential therapeutic targets. Transcriptomic data from TCGA and METABRIC confirmed our findings, with 10 of 11 observed pathways corroborated. Finally, differential expression of four immune-related surface proteins also suggested the potential of age-specific responses to immune-based therapies. Together, these findings may contribute to the understanding of the molecular mechanisms underlying worse outcomes in young women and offer new insight to therapeutic strategies.

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Publication Details

Journal
npj Breast Cancer
Published
2025-08-18
DOI
https://doi.org/10.1038/s41523-025-00793-0
Citations
3
Primary Topic
Breast Cancer Treatment Studies
Type
article
Field-Weighted Citation Impact
2.81

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article

Proteogenomic characterization of invasive breast tumors in young women

Harvey B. Pollard, Adelani Adeleye, Nicholas W. Bateman, Clifton L. Dalgard et al.
3 citations
npj Breast Cancer
Breast Cancer Treatment Studies
2.81
article

Proteogenomic characterization of invasive breast tumors in young women

Harvey B. Pollard, Adelani Adeleye, Nicholas W. Bateman, Clifton L. Dalgard, Mary Lou Cutler, Nicole De Wolf, Sean E. Hanlon, G. Larry Maxwell, Chunhua Yan, Camille Alba, Craig D. Shriver, Xiaoying Lin, Albert J. Kovatich, Jatinder Singh, Emanuel F. Petricoin, Elisa Baldelli, Trinh Duy Nguyen, Tamara Abulez, Brad Mostoller, Padma Sheila Rajagopal, Heather L. Blackburn, Brenda Deyarmin, Katherine M. Knapp, Coralie Viollet, Patricia S. Steeg, Anupama Praveen-Kumar, Sasha C. Makohon‐Moore, Lorraine Tafra, Leigh Fantacone-Campbell, Matthew D. Wilkerson, Stella Somiari, Jerez A. Te, Daoud Meerzaman, Dagmar Bačíková, Kathleen Darcy, Matthew Nealeigh, Glenn Gist, Brian L. Hood, David Sims, Julie Joseph, Stanley Lipkowitz, Kate Manley, Anthony R. Soltis, Mariaelena Pierobon, Alexandra S. Zimmer, Gauthaman Sukumar, Praveen Kumar, Mariano Russo, Jeffrey A. Hooke, Thomas P. Conrads, Leonid Kvecher, Lori A. Sturtz, Caroline Larson, Margaret M. Kildee, Victoria Olowu, Jerry Lee, Ying Hu, Xijun Zhang, Katie Miller, Hai Hu, Qingrong Chen, Jianfang Liu, J. Mitchell Wells, Dave Mitchell, Jennifer Kane, Katlin N. Wilson, Erinn McGrath, Kelly A. Conrads, Sraavya Polisetti, Melissa Cannada, Kimberly Murtha, Heather A. Kabala, Erin L. Goins, Jay Wareham, Lynn Mullican
article en
3 citations

Abstract

Breast cancer in women <40, accounting for ~5% of all breast cancer cases diagnosed in the U.S., is more aggressive and associated with worse outcomes compared to breast cancer in older women. We performed a first-ever integrated proteogenomic study from a matched cohort of laser-microdissected tumors of 34 young (<40 years) and 34 older (≥60 years) women to identify molecular features that may underlie the worse outcomes in young women. Progression-free interval was shorter in young women, and their tumors were enriched for more aggressive molecular subtypes. Our multi-omic analysis identified distinct clusters between age groups in luminal but not basal-like cancers. Notably, GATA3 mutations were enriched in luminal tumors from young women while TP53 and PIK3CA mutations were more common in luminal tumors from older women. Young women's tumors exhibited lower estrogen receptor (ER) expression yet paradoxically enhanced ER response pathways and increased expression of tamoxifen-resistance-associated genes (IRS1, FERMT1). Immune pathway activity and immune scores were lower in tumors from young women, whereas proliferative and MYC pathways were notably elevated, identifying potential therapeutic targets. Transcriptomic data from TCGA and METABRIC confirmed our findings, with 10 of 11 observed pathways corroborated. Finally, differential expression of four immune-related surface proteins also suggested the potential of age-specific responses to immune-based therapies. Together, these findings may contribute to the understanding of the molecular mechanisms underlying worse outcomes in young women and offer new insight to therapeutic strategies.

npj Breast CancerVol. 11(1)
QB3 (US), Inova Health System (US), University of Southern California (US), Henry M. Jackson Foundation (US), National Institutes of Health (US), Windber Research Institute (US), Uniformed Services University of the Health Sciences (US), George Mason University (US), Anne Arundel Medical Center (US), Walter Reed National Military Medical Center (US), Larry Ellison Foundation (US), Breast Center (CH), Division of Program Coordination Planning and Strategic Initiatives (US), National Cancer Institute (US), Center for Cancer Research (US)
U.S. Department of Defense, U.S. Department of Health and Human Services, Henry M. Jackson Foundation, National Institutes of Health, Uniformed Services University of the Health Sciences, National Cancer Institute
Openalex Percentile: Top 9%
Breast Cancer Treatment Studies
2.81
DOIOpen Access PDFOpenAlex
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