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 background expresses the c-neu oncogene under the control of a MMTV promoter in mammary tissue and appears to be a useful animal model for evaluation of strategies to delay or prevent mammary cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have delayed mammary cancer in the TG.NK model. Four week old hemizygous TG.NK female mice with MMTV/c-neu (erbB2) activated oncogene were fed NTP-2000 diet containing the retinoid analogue 4-hydroxyphenylretinamide (4-HPR) at 7 mmol/kg or the arotinoid Ro 40-8757 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 incidence markedly increased and was closer to the NTP-2000 diet control group. However, the 4-HPR diet markedly decreased the average weight of the tumors at 26 weeks with no decrease in multiplicity. The 4-HPR also caused significant increase in liver weights without an effect on body weight. Arotinoid Ro 40-8757 caused marked decrease in the number and branching of mammary ducts, and inhibited mammary tumor development with significant decrease in the incidence, multiplicity, and tumor weights compared to the NTP-2000 diet control. Arotinoid also caused a significant dose-related increase in liver weights without a significant effect on body weights. At the doses tested, 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, incidence, or absence of tumors when evaluated for any treatment group or for all mice in the study irrespective of treatment. The oncogene erbB2 (c-neu) and the growth factor EGF expression were more prominent in the small tumors of the mice treated with arotinoid than in the larger tumors of the control 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 retinoid analogues may be related to the delay in development of mammary glands.
Rao
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Environmental Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Ney
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Herbert
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D000818:Animals; D001835:Body Weight; D002471:Cell Transformation, Neoplastic; D004032:Diet; D004815:Epidermal Growth Factor / Q000096:biosynthesis*; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000473:pathology / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D012176:Retinoids / Q000494:pharmacology*
D012176:Retinoids; D004815:Epidermal Growth Factor