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

Abstract

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. 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, whereas control mice received the vehicle containing 10% dimethyl sulfoxide and 90% sunflower oil for the same duration as the treatment group. Mammary tumours were measured weekly over the 28 days and at termination, blood, mammary and lung tissue were collected for analysis. Mice with a tumour volume threshold of 4000mm3 were killed before the treatment regime was completed. 2‐ME treatment of early‐stage BC led to lower levels of mammary tumour necrosis, whereas 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. This study demonstrates that 2‐ME treatment has an antitumour effect on late‐stage BC, however, with no increase in survival rate, whereas the treatment failed to demonstrate any benefit in early‐stage BC.