Abstract
Approximately 30% of patients with estrogen receptor (ER) positive breast cancers exhibit de novo or intrinsic resistance to endocrine therapies. The purpose of this study was to define genes that distinguish ER+ resistant from ER+ responsive tumors, prior to the start of hormone therapies. Previously untreated post-menopausal patients with ER+ breast cancers were treated for 4 months in a neoadjuvant setting with the aromatase inhibitor exemestane alone, or in combination with the antiestrogen tamoxifen. Matched pre- and post-treatment tumor samples from the same patient, were analyzed by gene expression profiling and were correlated with response to treatment. Genes associated with tumor shrinkage achieved by estrogen blockade therapy were identified, as were genes associated with resistance to treatment. Prediction Analysis of Microarrays (PAM) identified 50 genes that can predict response or intrinsic resistance to neoadjuvant endocrine therapy of ER+ tumors, 8 of which have been previously implicated as useful biomarkers in breast cancer. In summary, we identify genes associated with response to endocrine therapy that may distinguish ER+, hormone responsive breast cancers, from ER+ tumors that exhibit intrinsic or de novo resistance. We suggest that the estrogen signaling pathway is aberrant in ER+ tumors with intrinsic resistance. Lastly, the studies show upregulation of a “lipogenic pathway” in non-responsive ER+ tumors that may serve as a marker of intrinsic resistance. This pathway may represent an alternative target for therapeutic intervention.
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Abbreviations
- ER:
-
Estrogen receptors
- PR:
-
Progesterone receptors
- AI:
-
Aromatase inhibitors
- R:
-
Responders
- NR:
-
Non-responders
- PLIN:
-
Perilipin
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Acknowledgments
This work was funded by a Department of Defense Clinical Bridge Award DAMD17-02-1-0353 (to J.K.R.); the National Institutes of Health (National Research Service Award F32 CA103511); United Negro College Fund/Pfizer grant (to D.M.E.H.); the National Institutes of Health Grant (RO1 CA26869), the National Foundation of Cancer Research, the Avon Foundation, and the Breast Cancer Research Foundation (to K.B.H.); and the National Institutes of Health Awards; R01-HD045962, P01-HD38129, R21-HD050863 (J.L.M.).
We acknowledge use of the University of Colorado Cancer Center Microarray Core and Computational Bioscience Program. We thank Carrie Greenwood for performing perilipin immunostaining.
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A commentary to this article is available at 10.1007/s10549-008-9923-6.
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Harvell, D.M.E., Spoelstra, N.S., Singh, M. et al. Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance. Breast Cancer Res Treat 112, 475–488 (2008). https://doi.org/10.1007/s10549-008-9897-4
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DOI: https://doi.org/10.1007/s10549-008-9897-4