Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ

Autor: Carol L. MacLeod, Lawrence J. T. Young, Robert D. Cardiff, Jeffrey P. Gregg, Alexander D. Borowsky, Michael W. DeGregorio, Ruria Namba, Gregory T. Wurz, Stephenie Liu, Erik T. McGoldrick, Jeannie E. Maglione
Rok vydání: 2005
Předmět:
Oncology
Aging
and promotion of well-being
Estrogen receptor
Noninfiltrating
Mice
chemistry.chemical_compound
0302 clinical medicine
Receptors
skin and connective tissue diseases
Cancer
0303 health sciences
3. Good health
Receptors
Estrogen
Selective estrogen receptor modulator
030220 oncology & carcinogenesis
Disease Progression
Stem Cell Research - Nonembryonic - Non-Human
Female
hormones
hormone substitutes
and hormone antagonists
Research Article
medicine.drug
Selective Estrogen Receptor Modulators
medicine.medical_specialty
Intraductal
Oncology and Carcinogenesis
Breast Neoplasms
Biology
Chemoprevention
Experimental
03 medical and health sciences
Rare Diseases
Ospemifene
Internal medicine
Breast Cancer
medicine
Carcinoma
Animals
Humans
Neoplasm Invasiveness
Oncology & Carcinogenesis
3.3 Nutrition and chemoprevention
030304 developmental biology
Prevention
Mammary Neoplasms
Mammary Neoplasms
Experimental
Ductal carcinoma
Stem Cell Research
Prevention of disease and conditions
Antiestrogen
medicine.disease
Estrogen
Transplantation
Tamoxifen
Carcinoma
Intraductal
Noninfiltrating
chemistry
Zdroj: Breast cancer research : BCR, vol 7, iss 6
Breast Cancer Research
ISSN: 1465-542X
DOI: 10.1186/bcr1317
Popis: Introduction Ductal carcinoma in situ (DCIS) is a noninvasive premalignant lesion and is considered a precursor to invasive carcinoma. DCIS accounts for nearly 20% of newly diagnosed breast cancer, but the lack of experimentally amenable in vivo DCIS models hinders the development of treatment strategies. Here, we demonstrate the utility of a mouse transplantation model of DCIS for chemoprevention studies using selective estrogen receptor modulators (SERMs). This model consists of a set of serially transplanted lines of genetically engineered mouse mammary intraepithelial neoplasia (MIN) outgrowth (MIN-O) tissue that have stable characteristics. We studied the ovarian-hormone-responsiveness of one of the lines with a particular focus on the effects of two related SERMs, tamoxifen and ospemifene. Methods The estrogen receptor (ER) status and ovarian-hormone-dependence of the mouse MIN outgrowth tissue were determined by immunohistochemistry and ovarian ablation. The effects of tamoxifen and ospemifene on the growth and tumorigenesis of MIN outgrowth were assessed at 3 and 10 weeks after transplantation. The effects on ER status, cell proliferation, and apoptosis were studied with immunohistochemistry. Results The MIN-O was ER-positive and ovarian ablation resulted in reduced MIN-O growth and tumor development. Likewise, tamoxifen and ospemifene treatments decreased the MIN growth and tumor incidence in comparison with the control (P < 0.01). Both SERMs significantly decreased cell proliferation. Between the two SERM treatment groups, there were no statistically significant differences in MIN-O size, tumor latency, or proliferation rate. In contrast, the ospemifene treatment significantly increased ER levels while tamoxifen significantly decreased them. Conclusion Tamoxifen and ospemifene inhibit the growth of premalignant mammary lesions and the progression to invasive carcinoma in a transplantable mouse model of DCIS. The inhibitory effects of these two SERMs are similar except for their effects on ER modulation. These differences in ER modulation may suggest different mechanisms of action between the two related SERMs and may portend different long-term outcomes. These data demonstrate the value of this model system for preclinical testing of antiestrogen or other therapies designed to prevent or delay the malignant transformation of premalignant mammary lesions in chemoprevention.
Databáze: OpenAIRE
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