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Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer.

ABSTRACT: Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially conducted gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of Wnt receptors, and its downstream targets LEF1 and TCF in residual CRL2335 tumor cells after treatment with cisplatin plus TRAIL. Increased FZD8 levels were further confirmed in other TNBC cell lines. Inhibition of FZD8 by siRNA in CRL2335 cells in the presence of cisplatin plus TRAIL reduced ?-catenin and survivin levels and increased apoptosis compared with scrambled siRNA-treated cells. In vivo data show that cisplatin plus TRAIL treatment significantly reduces tumor volume in NOD/SCID mice. However, we found that cisplatin plus TRAIL treatment predominantly eliminated non-tumor-initiating cells, as shown by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells stably transfected with DsRed. This led to TIC enrichment in residual tumors, as confirmed by immunostaining for TIC markers. Moreover, an increase in FZD8 expression was observed in residual tumors treated with cisplatin and TRAIL. Taken together, our findings suggest that FZD8-mediated Wnt signaling may play a major role in mediating resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBCs.

SUBMITTER: Yin S

PROVIDER: S-EPMC3624033 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer.

Yin Shuping S Xu Liping L Bonfil R Daniel RD Banerjee Sanjeev S Sarkar Fazlul H FH Sethi Seema S Reddy Kaladhar B KB

Molecular cancer therapeutics 20130227 4

Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially conducted gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant incre ...[more]

PMID: 23445611

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Project description:Obesity is a risk factor for triple-negative breast cancer (TNBC) incidence and poor outcomes, but the underlying molecular biology remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD variant 2 (MBD2_v2), is dependent on reactive oxygen species (ROS) and is crucial for maintenance and expansion of cancer stem cell-like cells (CSCs). Because obesity is coupled with inflammation and ROS, we hypothesized that obesity can fuel an increase in MBD2_v2 expression to promote the tumor-initiating CSC phenotype in TNBC cells in vivo. Analysis of TNBC patient datasets revealed associations between high tumor MBD2_v2 expression and high relapse rates and high body mass index (BMI). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD2_v2 expression is governed by ROS-dependent expression of serine- and arginine-rich splicing factor 2 (SRSF2). We employed a diet-induced obesity (DIO) mouse model that mimics human obesity to investigate whether obesity causes increased MBD2_v2 expression and increased tumor initiation capacity in inoculated TNBC cell lines. MBD2_v2 and SRSF2 levels were increased in TNBC cell line-derived tumors that formed more frequently in DIO mice relative to tumors in lean control mice. Stable MBD2_v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo. SRSF2 knockdown resulted in decreased MBD2_v2 expression, decreased CSCs in TNBC cell cultures, and hindered tumor formation in vivo. This report describes evidence to support the conclusion that MBD2_v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights into support of the epidemiological evidence that obesity is a risk factor for TNBC. The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity-linked cancers, which reinforces the relevance of this report.

Project description:BackgroundTreating triple-negative breast cancer (TNBC) is a difficult landscape owing to its short survival times and high risk of metastasis and recurrence among patients. Although involved in tumor invasion and metastasis, the mechanism of action of intercellular adhesion molecule 1 (ICAM1), a trans-membrane glycoprotein, in TNBC is ambiguous.MethodsWe examined ICAM1's role in TNBC, focusing on its expression, cell survival, mutation, and tumor immunity. Then, a risk score model was created utilizing co-expressed genes associated with ICAM1. According to their respective risk scores, we divided patients into high- and low-risk groups. Immune function, drug susceptibility differences, and somatic variants were analyzed in the high-and low-risk groups. And we used the CMap database to predict potential medications. Then, TNBC cells with low expression of ICAM-1 were co-cultured with PMA-treated THP-1 cells and CD8 T cells. In addition, We detected the expression of PD-1 and CTLA4 of low ICAM-1 expressing TNBC cells when they were cocultured with CD8 T cells.ResultsICAM1 was found to be involved in leukocyte cell adhesion, motility, and immune activation. Patients with low-ICAM1 group had shorter disease-free survival (DFS) than those with high-ICAM1 group. The group with elevated levels of ICAM1 exhibited significantly increased levels of T-cell regulation, quiescence in natural killer (NK) cells, and M1 macrophage. ICAM1 expression was correlated with immune checkpoint drugs. The prognostic ability of the risk score model was found to be superior to that of individual genes. Patients categorized as high-risk exhibited elevated clinical stages, showed higher M1 macrophage numbers, and were able to benefit better from immunotherapy. Individuals belonging to the high-risk group exhibit significantly elevated mutation rates in TP53, TTN, and SYNE1 genes, along with increased TMB and PD-L1 levels and decreased TIDE scores. These findings suggest that immunotherapy may be advantageous for the high-risk group. Furthermore, low expression of ICAM1 was found to promote polarization to M2 macrophages along with T-cell exhaustion.ConclusionIn conclusion, Low ICAM1 expression may be related to immune escape, leading to poor treatment response and a worse prognosis.

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Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer.

Publications

Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer.

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