Recent analyses of nearly 4,000 primary breast tumors characterized by multiple prognostic and predictive biomarkers support the basic premise that breast cancer biology is age-dependent. While breast cancer biomarkers reflecting genetic instability and tumor growth as well as receptors for growth factors and sex steroids vary significantly with patient age, others reflecting tumor angiogenic, invasive and proteolytic potential show no age association, calling into question current cancer-aging hypotheses. Among known age-dependent breast cancer biomarkers some (e.g. p53- positivity, apoptotic index) exhibit most of their variation after age 50, others (tumor cell proliferative indices) show most of their variation before age 60, while others (ErbB2, EGFR, ER) change almost continuously with increasing age. Notably, the marked age-dependent rise in tumor estrogen receptor (ER) overexpression is unaccompanied by comparable changes in ER-inducible gene expression (e.g. PR, pS2, Bcl2) and associated with enhanced oxidant stress-activated signaling (P-Erk5) and transcription factor dysfunction (loss of Sp1 DNA-binding), supporting two corollaries to our fundamental breast cancer and aging premise: i) age affects breast cancer biology even among histologically similar ER-positive, node-negative breast cancers, and ii) altered protein structure and function linked to oxidative stress and aging appear to clinically and biologically distinguish subsets of ER-positive breast cancers. To mechanistically distinguish ER-positive breast cancer subsets associated with aging, we will evaluate nucleic acid (DNA, RNA) and protein extracts from up to 264 cryobanked ER-positive node-negative ductal cancers arising in old (greater than age 70) vs. young (less than age 40) patients, with these age-grouped cases balanced for known risk factors and biomarkers linked to breast cancer incidence and biology. Since old and young ER-positive tumors are expected to use different p53-dependent and p53-independent mechanisms for growth dysregulation, CGH microarrays, PCR-based microsequencing and methylation status determinations will be used to document the extent and type of chromosomal gains/losses, p53 mutations, and epigenetic silencing defects in p21WAF1 and p14ARF/p161NK4 loci associated with higher tumor proliferative rates and distinguishing old vs. young cases. Since subgroups of ER-positive tumors increase differently with age and are associated with different clinical outcomes, RNA expression microarrays will be used to identify specific transcript profiles clustering with higher tumor proliferative rates within and between the age-defined tumor groups. Lastly, protein extracts from these same tumor groups, as well as from oxidant stress-induced breast cancer cell line models, will be used to confirm that critical differences defining the biology of ER-positive breast cancers arising in older patients include the enhanced role of tumor-promoting and oxidant stress-associated cell signaling (P-Erk5, p66Shc), intracellular protein damage (carbony content), and loss of Sp1 DNA-binding and ER/Sp1-driven gene expression. These DNA, RNA and protein studies are expected to identify new breast cancer biomarkers that may be used to tailor age-specific therapeutics and improve our understanding of critical subcellular mechanisms affected by aging, oxidative stress and malignant transformation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG020521-01A1
Application #
6606452
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Yancik, Rosemary
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$562,420
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
Yau, Christina; Wang, Yixin; Zhang, Yi et al. (2011) Young age, increased tumor proliferation and FOXM1 expression predict early metastatic relapse only for endocrine-dependent breast cancers. Breast Cancer Res Treat 126:803-10
Yau, Christina; Esserman, Laura; Moore, Dan H et al. (2010) A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer. Breast Cancer Res 12:R85
Atsriku, Christian; Britton, David J; Held, Jason M et al. (2009) Systematic mapping of posttranslational modifications in human estrogen receptor-alpha with emphasis on novel phosphorylation sites. Mol Cell Proteomics 8:467-80
Benz, Christopher C; Yau, Christina (2008) Ageing, oxidative stress and cancer: paradigms in parallax. Nat Rev Cancer 8:875-9
Benz, Christopher C (2008) Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol 66:65-74
Yau, Christina; Benz, Christopher C (2008) Genes responsive to both oxidant stress and loss of estrogen receptor function identify a poor prognosis group of estrogen receptor positive primary breast cancers. Breast Cancer Res 10:R61
Zhou, Yamei; Yau, Christina; Gray, Joe W et al. (2007) Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59
Yau, Christina; Fedele, Vita; Roydasgupta, Ritu et al. (2007) Aging impacts transcriptomes but not genomes of hormone-dependent breast cancers. Breast Cancer Res 9:R59
Campbell, Michael J; Esserman, Laura J; Zhou, Yamei et al. (2006) Breast cancer growth prevention by statins. Cancer Res 66:8707-14
Mattie, Michael D; Benz, Christopher C; Bowers, Jessica et al. (2006) Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 5:24

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