Triple-negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat due to a paucity of effective targeted therapies. Many studies have reported that breast cancer stem cells (BCSCs) are enriched in TNBC and are responsible for chemoresistance and metastasis. In this study, we identify LRP8 as a novel positive regulator of BCSCs in TNBC. LRP8 is highly expressed in TNBC compared to other breast cancer subtypes and its genomic locus is amplified in 24% of TNBC tumors. Knockdown of LRP8 in TNBC cell lines inhibits Wnt/β-catenin signaling, decreases BCSCs, and suppresses tumorigenic potential in xenograft models. LRP8 knockdown also induces a more differentiated, luminal-epithelial phenotype and thus sensitizes the TNBC cells to chemotherapy. Together, our study highlights LRP8 as a novel therapeutic target for TNBC as inhibition of LRP8 can attenuate Wnt/β-catenin signaling to suppress BCSCs.
Targeting cancer stem cells (CSCs) is a key strategy to prevent cancers from developing drug resistance and metastasis. Mitochondria have been reported to be a vulnerability of CSCs by multiple studies. Here, we report that doxycycline, functioning as an inhibitor of mitochondrial biogenesis, can effectively target breast cancer stem cells (BCSCs). Our results revealed that doxycycline significantly decreased the frequency of aldehyde dehydrogenase‑positive (ALDH+) BCSCs as well as mammosphere formation efficiency in HER2+ and triple‑negative breast cancer (TNBC) subtypes. Doxycycline also ameliorated paclitaxel‑induced enrichment of ALDH+ BCSCs in TNBC. Mechanistically, we showed that doxycycline decreased the level of reactive oxygen species and their downstream p38 MAPK pathway. In agreement with the key role for p38 in maintaining BCSCs, a specific inhibitor targeting this MAPK pathway significantly decreased the number of ALDH+ cells. Doxycycline is a FDA‑approved drug with minor and limited side‑effects. Given doxycycline's low toxicity and strong effect on BCSC inhibition, we report that doxycycline should be safe to be used concomitantly with chemotherapy drugs to eradicate both CSCs and bulk tumor cells.
Cancer stem cells (CSCs) are a small population of cancer cells that are capable of self-renewal and tumor initiation. As a result, targeting CSCs is a potential therapeutic strategy for preventing cancer relapse and metastasis. Mixed lineage kinase 4 (MLK4), a serine/threonine kinase, is known to regulate mesenchymal glioma stem cells and to drive tumorigenesis in colorectal cancer. We found that MLK4 was highly expressed in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes according to the database from The Cancer Genome Atlas. Furthermore, multiple datasets indicated that higher expression of MLK4 was associated with poor prognosis in breast cancer. Despite the correlation of MLK4 and clinical outcome, the function of MLK4 in breast cancer is still not known. In this study, we found that knockdown of MLK4 significantly decreased secondary mammosphere formation, the CD44+/CD24- CSC population, invasion and migration in TNBC cell lines. In addition to suppressing CSC phenotypes in vitro, knockdown of MLK4 also inhibited tumor growth in NOD/SCID mice. Secondary transplantation of tumor cells demonstrated that silencing of MLK4 significantly decreased tumor-initiating cell frequency. As accessed by qPCR, knockdown of MLK4 led to decreased expression of mesenchymal genes (CD44 and VIM) and concomitant increased expression of epithelial genes (CDH1 and claudin genes). Immunohistochemical staining revealed that knockdown of MLK4 in xenografts resulted in increased expression of CK19, a luminal-epithelial marker. These studies indicate that MLK4 plays an important role in the function of mesenchymal-like CSCs in TNBC. Silencing of MLK4 in TNBC cell lines can transform CSC in these tumors to a more differentiated epithelial cell state. Together, these studies identify that MLK4 is a potential therapeutic target for CSCs in TNBC. Citation Format: Chang-Ching Lin, Miao-Chia Lo, Rebecca Moody, Nicholas Stevers, Samantha Tinsley, Mari Gasparyan, Max Wicha, Duxin Sun. Identification of MLK4 as a novel regulator of cancer stem cells in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2004.
Tumor-initiating cells (TICs) are a small fraction of cancer cells that stands at the apex of the tumor hierarchy. Given their tumor-initiating ability and resistance to conventional chemotherapies, TICs are considered potential therapeutic targets for preventing the relapse and metastasis of malignancies. Our group has identified a novel gene, Cell division cycle associated 7 (CDCA7), as an important regulator of TICs in triple-negative breast cancer (TNBC). CDCA7 is a target gene of MYC and NOTCH. Ectopic expression of CDCA7 has been demonstrated to induce neoplastic transformation in vitro and tumorigenesis in vivo. Despite its potential tumor-initiating ability, CDCA7 has not yet been well-studied in breast cancer. We found that CDCA7 was highly expressed in TNBC compared to other subtypes of breast cancer according to the RNA-sequencing data from The Cancer Genome Atlas. Furthermore, our Kaplan-Meier analysis of multiple datasets demonstrated that higher expression of CDCA7 was associated with poor prognosis in breast cancer. When we knocked down CDCA7 by siRNA in TNBC cell lines including SUM149, HCC1937, MDA-MB-231, and MDA-MB-436, CD44+/CD24- stem-like cell population and primary and secondary mammosphere formation were significantly decreased. In addition to suppressing the stem-like properties, knockdown of CDCA7 also inhibited the invasion and migration of breast cancer cells. These phenotypes indicated the inhibition of epithelial-to-mesenchymal transition (EMT), which was in accordance with the up-regulation of E-Cadherin and down-regulation of Vimentin after CDCA7 knockdown in TNBC cell lines. In conclusion, our results have demonstrated that CDCA7 is an important regulator of TICs in TNBC. Loss-of-function of CDCA7 leads to the inhibition of EMT and stemness in TNBC cells. Citation Format: Chang-Ching Lin, Miao-Chia Lo, Rebecca Moody, Nicholas Stevers, Samantha Tinsley, Max Wicha, Duxin Sun. Identifying CDCA7 as a novel regulator of tumor-initiating cells in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4767. doi:10.1158/1538-7445.AM2017-4767
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