Abstract
We seek to evaluate the clinical consequences of resistance to antihormonal therapy by studying analogous animal xenograft models. Two approaches were taken: (1) MCF-7 tumors were serially transplanted into selective estrogen receptor modulator (SERM)-treated immunocompromised mice to mimic 5 years of SERM treatment. The studies in vivo were designed to replicate the development of acquired resistance to SERMs over years of clinical exposure. (2) MCF-7 cells were cultured long-term under SERM-treated or estrogen withdrawn conditions (to mimic aromatase inhibitors), and then injected into mice to generate endocrine-resistant xenografts. These tumor models have allowed us to define Phase I and Phase II antihormonal resistance according to their responses to E2 and fulvestrant. Phase I SERM-resistant tumors were growth stimulated in response to estradiol (E2), but paradoxically, Phase II SERM and estrogen withdrawn-resistant tumors were growth inhibited by E2. Fulvestrant did not support growth of Phases I and II SERM-resistant tumors, but did allow growth of Phase II estrogen withdrawn-resistant tumors. Importantly, fulvestrant plus E2 in Phase II antihormone-resistant tumors reversed the E2-induced inhibition and instead resulted in growth stimulation. These data have important clinical implications. Based on these and prior laboratory findings, we propose a clinical strategy for optimal third-line therapy: patients who have responded to and then failed at least two antihormonal treatments may respond favorably to short-term low-dose estrogen due to E2-induced apoptosis, followed by treatment with fulvestrant plus an aromatase inhibitor to maintain low tumor burden and avoid a negative interaction between physiologic E2 and fulvestrant.
Original language | English (US) |
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Pages (from-to) | 128-138 |
Number of pages | 11 |
Journal | Journal of Steroid Biochemistry and Molecular Biology |
Volume | 102 |
Issue number | 1-5 SPEC. ISS. |
DOIs | |
State | Published - Dec 2006 |
Externally published | Yes |
Keywords
- Breast cancer
- Estradiol
- Fulvestrant
- Raloxifene
- Tamoxifen
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Endocrinology
- Clinical Biochemistry
- Cell Biology