Prevention of HER-2/neu transgenic mammary carcinoma by tamoxifen plus interleukin 12.
FVB-NeuN (N#202) female mice transgenic for the HER-2/neu protooncogene driven by the murine mammary tumor virus (MMTV) promoter develop mammary carcinomas with a progression from focal atypical hyperplasia to in situ carcinoma and to invasive carcinoma that closely resembles that of human neoplasia. Here we report that the combination of tamoxifen plus interleukin 12 (IL-12) results in a very effective prevention of mammary carcinogenesis, significantly higher than those obtained with either tamoxifen or IL-12 alone. At 1 year of age, 20% of control mice resulted tumor-free, whereas 80% of mice receiving the combined treatment were tumor-free. At 2 years of age, less than 5% of control mice were tumor-free, as opposed to 70% of mice treated with tamoxifen plus IL-12. The combined treatment inhibited mammary carcinogenesis mainly through a reduction in the number of mammary cells at risk of progression, a reduction in estrogen receptors (ERs) expression and a reduction in the angiogenic support to mammary development, likely due to cross-talk between tamoxifen and interferon-gamma (IFN-gamma) (the main downstream mediator elicited in vivo by IL-12). The addition of IL-12 to the tamoxifen treatment more than doubled mouse lifetime and did not exacerbate known side effects of tamoxifen.
Nanni
Patrizia
P
Cancer Research Section, Department of Experimental Pathology, University of Bologna, Bologna, Italy.
Nicoletti
Giordano
G
De Giovanni
Carla
C
Landuzzi
Lorena
L
Di Carlo
Emma
E
Iezzi
Manuela
M
Ricci
Cinzia
C
Astolfi
Annalisa
A
Croci
Stefania
S
Marangoni
Francesco
F
Musiani
Piero
P
Forni
Guido
G
Lollini
Pier-Luigi
PL
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001940:Breast / Q000473:pathology; D002277:Carcinoma / Q000473:pathology* / Q000517:prevention & control*; D005260:Female; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage*; D015674:Mammary Neoplasms, Animal / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage* / Q000494:pharmacology; D013997:Time Factors
D000276:Adjuvants, Immunologic; D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D007371:Interferon-gamma; D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen