Effect of 2-methoxyestradiol treatment on early- and late-stage breast cancer progression in a mouse model

Abstract

BACKGROUND: The prevalence of breast cancer (BC) continues to increase and is the leading cause of cancer deaths in many countries. Numerous in vitro and in vivo studies have demonstrated that 2-methoxyestradiol (2-ME) has antiproliferative and antiangiogenic effects in BC thereby inhibiting tumour growth and metastasis. We compared the effect of 2-ME in early and late-stage BC using a transgenic mouse model – FVB/N-Tg(MMTV-PyVT) – of spontaneously development of aggressive mammary carcinoma with lung metastasis. METHODS: Mice received 100 mg/kg 2-ME treatment immediately when palpable mammary tumours were identified (early-stage BC; experimental group 1) and 28 days after palpable mammary tumours were detected (late-stage BC; experimental group 2). 2-ME was administered via oral gavage three times a week for 28 days after initiation of treatment, while control mice received the vehicle containing 10% dimethyl sulfoxide (DMSO) and 90% sunflower oil for the same duration as the treatment group. Mammary tumours were measured weekly over the 28-day period and at termination, blood, mammary and lung tissue were collected for analysis. Mice with a tumour volume threshold of 4000mm3 were euthanized before the treatment regime was completed. RESULTS: 2-ME treatment of early-stage BC led to lower levels of mammary tumour necrosis, while tumour mass and volume were increased. Additionally, necrotic lesions and anti-inflammatory CD163 expressing cells were more frequent in pulmonary metastatic tumours in this group. In contrast, 2-ME treatment of late-stage BC inhibited tumour growth over the 28-day period, and resulted in increased CD3+ cell number and tumour necrosis. Furthermore, 2-ME treatment slowed down pulmonary metastasis, but did not increase survival of late-stage BC mice. Besides late-stage tumour necrosis, none of the other results were statistically significant. CONCLUSION: This study demonstrates that 2-ME treatment has an antitumour effect on late-stage BC, however with no increase in survival rate, while the treatment failed to demonstrate any benefit in early-stage BC.