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The Effect of Cigarette Smoke Exposure on Pulmonary Metastatic Disease in a Murine Model of Metastatic Breast Cancer^*

^* From the Division of Pulmonary and Critical Care Medicine (Dr. Murin), Department of Internal Medicine, Department of Cell Biology and Human Anatomy (Drs. Hubbard and Erickson), University of California Davis School of Medicine, Davis, CA; and Center for Health and the Environment (Dr. Pinkerton), University of California, Davis, CA.

Correspondence to: Susan Murin, MD, MSc, FCCP, 4150 V St, Suite 3400, Sacramento, CA 95817; e-mail: sxmurin{at}ucdavis.edu

Introduction: Women who smoke have a higher rate of fatal breast cancer than nonsmoking women. An association between smoking and pulmonary metastases from breast cancer has been suggested by epidemiologic studies.

Study objectives: To examine the relationship between exposure to cigarette smoke and pulmonary metastasis in a murine model of metastatic mammary cancer.

Study design: Prospective, randomized study.

Setting: Animal research laboratory.

Experimental subjects: Female sexually mature BALB/cAnN mice.

Interventions: Mice were randomly divided into experimental and control groups. Experimental animals were exposed to cigarette smoke in specialized exposure chambers, at concentrations chosen to approximate active cigarette smoking. Control animals were exposed to filtered air. One week after the initiation of exposures, mouse mammary tumor cells (tumor cell line 4526) were injected into the tail veins of experimental animals at one of three concentrations (50,000, 100,000, or 150,000 cells per 100 µL). Three weeks later, the mice were killed, and pulmonary metastases were counted and measured.

Results: The mean metastatic burden in the lungs was consistently greater for smoke-exposed animals at each concentration of cells injected (at 50,000 cells per 100 µL, 9.8 vs 4.8 µm³, respectively [p < 0.01]; at 100,000 cells per 100 µL, 34.5 vs 17.4 µm³, respectively [p < 0.10]; and at 150,000 cells per 100 µL, 54.0 vs 31.5 µm³, respectively [p < 0.05]). This was largely attributable to a significant increase in the number of metastatic nodules per animal (at 50,000 cells per 100 µL, 8.7 vs 4.8, respectively [p < 0.001]; at 100,000 cells per 100 µL, 24.3 vs 14.0, respectively [p > 0.10]; and at 150,000 cells per 100 µL, 42.0 vs 20.1, respectively [p < 0.02]) rather than to a change in nodule size.

Conclusions: Cigarette smoke exposure is associated with an increase in the total pulmonary metastatic burden in this murine model of metastatic mammary cell cancer. This study provides experimental support for an adverse effect of smoking on the metastatic process and suggests a possible mechanism for smokers’ increased breast cancer mortality.

Key Words: breast cancer • metastasis • smoking