Abstract
Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial–mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration.
Highlights
Breast cancer is the most commonly diagnosed cancer and the second-largest cause of cancer-related deaths in women in the United States [1]
Triple negative breast cancers (TNBCs) are defined through their lack of these receptors and are more difficult to manage clinically owing to the lack of protein targets, in contrast to tumors with hormone receptor or human epidermal growth factor receptor 2 (HER2) positive breast cancer, which are conventionally targeted with hormone inhibitors such as estrogen-response modulators and aromatase inhibitors or HER2-blocking antibodies, respectively [2]
These studies have relied on constitutive overexpression of miR-203, and do not mimic what could be achievable in a clinical setting
Summary
Breast cancer is the most commonly diagnosed cancer and the second-largest cause of cancer-related deaths in women in the United States [1]. A majority of breast cancers are carcinomas, and their histological stratification is based primarily on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Triple negative breast cancers (TNBCs) are defined through their lack of these receptors and are more difficult to manage clinically owing to the lack of protein targets, in contrast to tumors with hormone receptor or HER2 positive breast cancer, which are conventionally targeted with hormone inhibitors such as estrogen-response modulators and aromatase inhibitors or HER2-blocking antibodies, respectively [2]. Most breast cancer patients do not succumb to their primary tumor, but instead to metastases that become apparent after the primary lesion has been removed. For cells to contribute to metastases they must leave the primary site, enter the vasculature, survive in the blood, and extravasate, and colonize secondary sites. Despite metastasis being a complex, multistep process, clinical and experimental evidence supports a role for epithelial–mesenchymal transition (EMT) in driving metastasis [3,4,5,6]
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