Development and Therapeutic Options for the Treatment of Raloxifene-Stimulated Breast Cancer in Athymic Mice

• Published in: Clinical cancer research Vol. 12; no. 7; pp. 2255 - 2263
• Main Authors: O'REGAN, Ruth M, OSIPO, Clodia, ARIAZI, Eric, EUN SOOK LEE, MEEKE, Kathleen, MORRIS, Caroline, BERTUCCI, Anne, SARKER, Mohammad A. B, GRIGG, Ronald, JORDAN, V. Craig
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2006
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Cell Proliferation - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Neoplasm - drug effects; ERα; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Receptor alpha - drug effects; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Gene Expression Regulation, Neoplastic - drug effects; Genes, erbB-2 - drug effects; Genes, erbB-2 - genetics; Gynecology. Andrology. Obstetrics; HER2; Humans; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - therapy; neu; Pharmacology. Drug treatments; Quinazolines - pharmacology; Raloxifene; Raloxifene Hydrochloride - administration & dosage; Raloxifene Hydrochloride - therapeutic use; Resistance; RNA, Messenger - drug effects; RNA, Messenger - genetics; Structure-Activity Relationship; Transplantation, Heterologous; Trastuzumab; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Estrogen receptor; Antiestrogen; Rodentia; Breast cancer; Antihormone; Malignant tumor; Benzothiophene derivatives; Mammary gland diseases; Vertebrata; Mammalia; Treatment; Mouse; Animal; Raloxifene; Agonist antagonist; Non steroid compound; Hormonal receptor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2584

Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor α (ERα) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17β-estradiol. Epidermal growth factor receptor/HER1 and HER2/ neu mRNAs were increased in MCF-7RALT tumors. The HER2/ neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo . Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/ neu , total HER2/ neu , phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERα protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERα activity of MCF-7RALT tumors. The coactivator of ERα, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERα in cells derived from the MCF-7RALT tumors. Conclusions: These results suggest that overexpression and increased activity of HER2/ neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERα could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERα activity.