Abstract
Mitochondria play important roles in cancer progression and have emerged as viable targets for cancer therapy. Increasing levels of the outer mitochondrial membrane protein, 18-kDa translocator protein (TSPO), are associated with advancing breast cancer stage. In particular, higher TSPO levels are found in estrogen receptor (ER)-negative breast tumors, compared with ER-positive tumors. In this study, we sought to define the roles of TSPO in the acquisition of breast cancer malignancy. Using a three-dimensional Matrigel culture system, we determined the impact of elevated TSPO levels on mammary epithelial morphogenesis. Our studies demonstrate that stable overexpression of TSPO in mammary epithelial MCF10A acini drives proliferation and provides partial resistance to luminal apoptosis, resulting in enlarged acinar structures with partially filled lumen that resemble early stage breast lesions leading to breast cancer. In breast cancer cell lines, TSPO silencing or TSPO overexpression significantly altered the migratory activity. In addition, we found that combination treatment with the TSPO ligands (PK 11195 or Ro5-4864) and lonidamine, a clinical phase II drug targeting mitochondria, decreased viability of ER-negative breast cancer cell lines. Taken together, these data demonstrate that increases in TSPO levels at different stages of breast cancer progression results in the acquisition of distinct properties associated with malignancy. Furthermore, targeting TSPO, particularly in combination with other mitochondria-targeting agents, may prove useful for the treatment of ER-negative breast cancer.
Highlights
Breast cancer is the second most frequently diagnosed cancer and one of the leading causes of cancer death among U.S women [1]
The levels of ectopically expressed and endogenous translocator protein (TSPO) in the stable MCF10A populations were evaluated by immunoblotting using an anti-FLAG (Fig. 1A, top panel) or anti-TSPO antibody (Fig. 1A, bottom panel)
Total TSPO levels were 2.5 fold higher in the MCF10A-TSPO population compared to the control MCF10A-pLXSN population
Summary
Breast cancer is the second most frequently diagnosed cancer and one of the leading causes of cancer death among U.S women [1]. Estrogen receptor (ER)-negative breast cancers are typically more aggressive than ER-positive tumors [2,3]. In the absence of HER2 overexpression, there are no currently available targeted therapies to treat ER-negative breast cancer. Chemotherapeutic agents can be useful in treating patients with ER-negative breast tumors but resistance and toxicity limit efficacy [1,2,4]. Mitochondria play central roles in regulating bioenergetics, metabolism and cell death. Targeting mitochondria has emerged as a potential strategy for breast cancer therapy [5,7]
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