Changes associated with delay of mammary cancer by retinoid analogues in transgenic mice bearing c-neu oncogene

Breast cancer is one of the common cancers and is a leading cause of cancer mortality in women. The TG. NK transgenic mouse line on FVB strain backgro und expresses the c-neu oncogene under the control of a MMTV promoter in ma mmary tissue and appears to be a useful animal model for evaluation of stra tegies to delay or prevent mammary cancer. Fiber-rich nonpurified diet (NTP -2000) and some retinoid analogues have delayed mammary cancer in the TG. N K model. Four week old hemizygous TG. NK female mice with MMTV/c-neu (erbB2 ) activated oncogene were fed NTP-2000 diet containing the retinoid analogu e 4-hydroxyphenylretinamide (4-HPR) at 7 mmol/kg or the arotinoid Ro 40-875 7 at 1.5 and 2.5 mmol/kg for 26 weeks. The 4-HPR at 7 mmol/kg diet delayed the development of palpable tumors up to 24 weeks, but by 26 weeks, the inc idence markedly increased and was closer to the NTP-2000 diet control group . However, the 4-HPR diet markedly decreased the average weight of the tumo rs at 26 weeks with no decrease in multiplicity. The 4-HPR also caused sign ificant increase in liver weights without an effect on body weight. Arotino id Ro 40-8757 caused marked decrease in the number and branching of mammary ducts, and inhibited mammary tumor development with significant decrease i n the incidence, multiplicity, and tumor weights compared to the NTP-2000 d iet control. Arotinoid also caused a significant dose-related increase in l iver weights without a significant effect on body weights. At the doses tes ted, the arotinoid but not 4-HPR decreased the circulating levels of IGF-1. However, there was no association between the IGF-1 levels and the size, i ncidence, or absence of tumors when evaluated for any treatment group or fo r all mice in the study irrespective of treatment. The oncogene erbB2 (c-ne u) and the growth factor EGF expression were more prominent in the small tu mors of the mice treated with arotinoid than in the larger tumors of the co ntrol group. PCNA staining was observed in areas where there was high erbB2 and EGF staining. The delay in onset of mammary tumors by the above retino id analogues may be related to the delay in development of mammary glands.