Mini-reviewPathways to tamoxifen resistance
Section snippets
Endocrine therapies for breast cancer
Estrogen and the steroid estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Mammals express two ERs, ERα and ERβ, which show distinct tissue distributions and functions (for review, see [1]). Mice with targeted deletions of one or both ER genes have established that ERα is the key regulator of mammary gland development. ERα is expressed in 15–30% of the luminal epithelial cells present in normal breast tissue; estrogen
Molecular mechanisms of antiestrogen resistance
Emerging data from breast tumor biopsies indicate that altered expression and/or modification of several growth factor receptors and downstream signaling molecules correlate with tamoxifen resistance (Fig. 1). Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor type 2 (HER2), and insulin-like growth factor-1 receptor (IGF-1R) signaling pathways are often elevated in non-responsive tumors that exhibit either de novo or acquired resistance [27], [28], [29], [30], as is
Endocrine therapies; effect on motility/invasion/metastasis
Metastatic breast cancer is ultimately the greatest cause of disease mortality. Tamoxifen is beneficial for decreasing secondary disease occurrence, both at local and distant sites [178]. However, the major phenotype of endocrine resistance is cancer recurrence. While clinical data have not definitively linked antiestrogen resistance with metastasis, many of the proteins/pathways discussed above in Section 2 that are involved in circumventing antiestrogen-induced blocks in cell cycle
Prediction of response
It is clear from the discussion above that resistance to endocrine therapy likely occurs through diverse mechanisms that vary from patient to patient. Consequently, it is imperative to develop molecular signatures that can predict the likelihood of response and potential for relapse of individual tumors. Initially, predictive markers for tamoxifen resistance included expression of ER and receptor tyrosine kinases such as EGFR and HER2. As our understanding of antiestrogen resistance has
Acknowledgments
The authors acknowledge support of our research from the Susan G. Komen Breast Cancer Foundation (PDF0503551) and Department of Defense Breast Cancer Research Program (BC051851) to RBR, the Department of Defense Breast Cancer Research Program (BC050339) to RSS, the National Cancer Institute institutional training Grant (T32 CA009109) for R.S.S. and M.S.G.; and the National Institutes of Health (R01 CA 096846) to AHB and R01 CA 123037 to Sarah J. Parsons, AHB Co-PI).
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