Abstract
Triple-negative breast cancer (TNBC) refers to a group of biologically aggressive breast cancers that do not express estrogen, progesterone or epidermal growth factor receptor 2 hormone receptors. Each subset of TNBC has a unique molecular profile and may require specific treatments. A combination of surgery and chemotherapy followed by radiation therapy is the standard treatment mode for TNBC patients. Tumor oxygen status (hypoxia) is a key factor that may compromise the effectiveness of radiation treatment, as it is known that hypoxia can confer radiation resistance. In this study, we characterized MDA-MB-231 orthotropic xenograft tumors with respect to tumor oxygen level and their response to supplemental oxygen therapy in combination with paclitaxel and radiation therapy. We observed that the TNBC tumors became severely hypoxic (pO2 < 4 mmHg) within 1 week of tumor growth and responded poorly to administration of respiratory hyperoxygenation (100% O2) to mitigate hypoxia. However, periodic administration of supplemental oxygen (100% O2; 60 min/day for 21 days) showed a significant inhibitory effect on tumor volume when compared to control (1,023 ± 32 mm3 vs. 1,378 ± 114 mm3; p < 0.05). Combination of supplemental oxygen with paclitaxel and radiation therapy led to a significant reduction in tumor growth when compared to radiation alone (239 ± 40 mm3 vs. 390 ± 32 mm3; p < 0.05). The therapeutic enhancement by supplemental oxygen is possibly attributed to increase in tumor oxygenation with paclitaxel at the time of radiation treatment. These findings may have important implications in the understanding of the role of oxygen and supplemental oxygen therapy for the treatment of TNBC patients.
Highlights
Breast cancer is the most common cancer among women worldwide, with an estimated 30% of new cancer cases in 2018 [1]
Our findings indicate that while triple-negative breast cancer (TNBC) is severely hypoxic, a combination of Pax and hyperoxygenation therapy can mitigate this hypoxia to a statistically non-significant level but have biologically significant effects when combined with radiation therapy
These findings could potentially be introduced into the clinic safely and quickly, with the goal of improving patient survival
Summary
Breast cancer is the most common cancer among women worldwide, with an estimated 30% of new cancer cases in 2018 [1]. Breast cancers are generally classified based on their hormone receptor status, namely, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). There is a subtype of breast cancer that has none of these receptors, called triple-negative breast cancer (TNBC), which accounts for about 15% of all types of breast cancer. TNBC is a very aggressive cancer and is found very frequently in young women and women of African-American descent [2, 3]. Hormone-positive breast cancers can be treated with a variety of drugs that exploit the reliance of these types of cancers on hormone signaling [4].
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