Abstract
Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment.
Highlights
Breast cancer is a major disease for which more effective and efficient therapies need to be developed
The ratio of micro RNA 100 (miR-100) level in a tumor to that in matched normal control, which indicates the extent of miR-100 downregulation, was significantly smaller in luminal A tumors than in other tumors (Figure 1A), indicating that miR-100 downregulation was more extensive in the luminal A subtype of breast cancer
MiR-100 was downregulated in these breast cancers, and the downregulation was more pronounced in luminal A breast cancers than in other subtypes of tumors (Figure 1B)
Summary
Breast cancer is a major disease for which more effective and efficient therapies need to be developed. While luminal A breast cancers generally have a good prognosis and respond well to hormonal therapies, they do not appear to benefit from the addition of the microtubule-targeted chemotherapy drug paclitaxel [2, 6,7,8]. While miR-100 regulates β-tubulin isotypes in MCF-7 breast cancer cells [23], and tubulin alteration is a known mechanism for breast cancer resistance to the microtubule-targeted drug paclitaxel [24], luminal A breast cancers are less responsive to paclitaxel treatment, and the role of miR-100 in paclitaxel response is unknown. While miR-100 inhibits the self-renewal of breast cancer stem-like cells (BrCSCs) and sensitizes basal-like breast cancer stem cells to hormonal therapy by promoting cell differentiation [25, 26], whether miR-100 has different effects on different subtypes of breast cancer remains unknown
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