The Effect of Chronic Cadmium Exposure on Chemotherapy Sensitivity in Breast Cancer Cells

Abstract

Breast cancer is a leading cause of cancer‐related mortality among women in the United States. Exposure to environmental carcinogens, such as cadmium, has been shown to increase the risk of breast cancer. While humans are only exposed to cadmium at minute quantities through diet and cigarette smoke, it tends to bioaccumulate in the body. Epidemiological studies have shown that patients with breast cancer tend to have higher levels of cadmium in comparison to healthy patients. Previous findings from our lab indicate that breast cancer cells chronically exposed to low levels of cadmium (MCF7‐Cd) had altered gene expression profiles and higher rates of cell growth, migration, and invasion compared to the parental cells (MCF7). Despite evidence suggesting chronic cadmium exposure promotes breast cancer progression, its effect on therapeutic response is largely unknown. Here we evaluate the effects of chronic cadmium exposure on the ability of breast cancer cells to response to different classes of cancer therapeutics—antiestrogens (tamoxifen and endoxifen), taxanes (cabazitaxel and docetaxel), an anthracycline (doxorubicin), and an antimetabolite (gemcitabine). Our results suggest that cells chronically exposed to cadmium (MCF7‐Cd7 and ‐Cd12) did not show a differential response to antiestrogens, doxorubicin, or gemcitabine. Interestingly, MCF7‐Cd7 and ‐Cd12 cells did exhibit decreased response to the taxanes in comparison to the parent MCF7 cells (GI50 of 11.34 nM and 15.12 nM, respectively, vs. GI50 of 4.04 nM) suggesting that chronic cadmium exposure contributes to the development of taxane resistance. Analysis at the protein level indicate that 1 nM of cabazitaxel or docetaxel was sufficient to induce PARP cleavage—a signal of apoptosis— in MCF7 cells, while PARP cleavage was not evident in MCF7‐Cd7 and ‐Cd12 cells until 5 and 10 nM, respectively. Consistent with this finding, the expression of p53 and p21 were concordantly increased in response to 1 nM of cabazitaxel or docetaxel in MCF7 cells, but expression did not increase in the cadmium‐adapted cells until a higher taxane concentration. Collectively, this data strongly suggest that chronic cadmium exposure may contribute to the development of resistance to taxane‐induced apoptosis, and does not alter sensitivity to the other cancer drugs. Further work is necessary to understand the mechanism of this drug resistance and the potential implications in the treatment of breast cancer.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.