Cell, Tumor, and Stem Cell Biology
Influence of Antibiotic Treatment on Breast Carcinoma Development in Proto-neu Transgenic Mice
Anna Rossini1, Cristiano Rumio2, Lucia Sfondrini3, Elda Tagliabue1, Daniele Morelli1, Rosalba Miceli1, Luigi Mariani1, Marco Palazzo2, Sylvie Ménard1 and Andrea Balsari3
1 Molecular Targeting Unit, Medicine Laboratory Unit, and Unit of Medical Statistics and Biometry, Department of Experimental Oncology and Laboratories, National Cancer Institute; 2 Department of Human Morphology and 3 Institute of Pathology, University of Milan, Milan, Italy
Requests for reprints: Andrea Balsari, Institute of Pathology, University of Milan, Via Mangiagalli, 31, Milan, Italy. Phone: 39-02-23902564; E-mail:
andrea.balsari@unimi.it.
The effect of prolonged antibiotic treatments on tumor development was evaluated in proto-neu transgenic mice, which spontaneously develop mammary carcinomas. Virgin transgenic mice were treated with metronidazole/ciprofloxacin or gentamicin through the drinking water. The hazard ratio [HR; 95% confidence interval (95% CI)] of breast cancer occurrence in metronidazole/ciprofloxacin-treated mice was more than triple that for controls [3.11 (1.13-8.53); P = 0.028], whereas only a slight increase in HR (95% CI) was observed in gentamicin-treated mice [1.39 (0.56-3.47); P = 0.481]. Tumor growth rate in gentamicin-treated mice was significantly faster than in untreated control mice (P = 0.043). Moreover, mammary glands from mice treated with either antibiotic regimen showed increased lobulization, with more numerous and more developed terminal ductal lobular units than in controls. These results indicate that prolonged exposure to relevant doses of antibiotics affects the mammary glands in this particular model of HER-2/neu transgenic mice; further studies to understand the precise mechanism by which antibiotic treatments influence mammary gland differentiation are critical. (Cancer Res 2006; (12): 6219-24)
Some epidemiologic studies have suggested a positive association between antibiotic use and risk of breast cancer (1, 2). A Finnish population study found that premenopausal women who used antibiotics for urinary tract infections had an elevated risk of breast cancer compared with women who did not use antibiotics; the age-adjusted relative risk [95% confidence interval (95% CI)] was 1.34 (098-1.83) and the risk for women ages <50 years was 1.74 (1.13-2.68; ref. 1). In a North American population study (2), cumulative days of antibiotic use were associated with increased risk of breast cancer, with an estimated odds ratio (95% CI) of 2.07 (1.48-2.88) in women who underwent long-term (>1,001 days) antibiotic treatment. In that study, all classes of antibiotics were associated with increased breast cancer risk and the association persisted after adjustment for factors, such as family history of breast cancer, age at menarche, age at birth of first child, age at menopause, postmenopausal estrogen-replacement therapy, cigarette smoking, alcohol intake, and dietary fat intake (2). Other studies have found either no clear association between breast cancer and antibiotic use (3, 4) or a low association (5) between breast cancer and a specific antibiotic, such as flucloxacillin, which is commonly used to treat breast cancer abscess and mastitis (6). Thus, it remains unclear whether antibiotic use is causally related to breast cancer or whether there are common mediators of antibiotic exposure and breast cancer. Indeed, some women may have underlying immune or inflammatory disorders that predispose them to neoplasia, and antibiotic use would only be a marker for impaired immune function or for underlying infections.
Activation of the HER family of growth factor receptors and subsequent stimulation of their associated intracellular signaling pathways is a significant factor in the genesis of several human cancers (7). Amplification of the HER-2/neu gene and consequent protein overexpression occurs in 25% to 30% of primary human breast tumors and is associated with poor prognosis (8, 9). The oncogenic potential of HER-2/neu has been confirmed in mammary epithelia of transgenic mice (10, 11). In these mice, the presence of the rat neu proto-oncogene driven by the mouse mammary tumor virus promoter/enhancer induces spontaneous multifocal mammary tumors overexpressing the neu-encoded p185 protein in all females (12). The stochastic development of the tumors and the long latency period indicate the requirement for additional events in tumor formation. We reasoned that if antibiotic treatment is causally related to breast cancer, antibiotic treatment in an animal model with a genetic predisposition to develop mammary tumors might increase the occurrence of breast carcinoma. We thus evaluated the role of prolonged antibiotic treatments on tumor development in HER-2/neu proto-oncogene transgenic female mice...
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