CD44(+)/CD24(-/low) cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome.
ABSTRACT Women classified as having triple-negative tumors have a poor prognosis. The importance of CD44(+)/CD24(-/low) (stem/progenitor cell-phenotype) in breast cancer patients has also been appreciated. However, correlation between triple negativity and CD44(+)/CD24(-/low) with tumor recurrence remains elusive. In the present study, we evaluated tumor specimens of 50 breast cancer patients with known hormone receptor status for whom we had follow-up information and outcome data available, and performed immunohistochemistry analysis to determine CD44 and CD24 expression. Gene expression arrays were also independently performed on 52 breast cancer specimens with banked frozen tissue. Lastly, we used FVBN202 transgenic mouse model of breast carcinoma and determined the hormone receptor status, the proportion of CD44(+)/CD24(-/low) breast cancer stem-like cells, and the behavior of the tumor. We determined that patients with triple-negative tumors had significantly higher incidence of recurrence or distant metastasis associated with increased frequency of breast cancer stem cell phenotypes compared with those with non-triple-negative tumors. Preclinical studies in FVBN202 transgenic mice confirmed these findings by showing that relapsed tumors were triple negative and had significantly higher frequency of breast cancer stem cells compared with their related primary tumors. Unlike non-triple-negative primary tumors, relapsed triple-negative tumors were tumorigenic at low doses when inoculated into FVBN202 transgenic mice. These findings suggest that CD44(+)/CD24(-/low) breast cancer stem-like cells play an important role in the clinical behavior of triple-negative breast cancer and that development of therapeutic targets directed to breast cancer stem-like cells may lead to reduction in the aggressiveness of triple-negative breast cancers.
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ABSTRACT: Basal-like breast cancer is an aggressive tumor subtype with a poor response to conventional therapies. Tumor formation and relapse are sustained by a cell subset of Breast Cancer Stem Cells (BrCSCs). Here we show that miR-100 inhibits maintenance and expansion of BrCSCs in basal-like cancer through Polo-like kinase1 (Plk1) down-regulation. Moreover, miR-100 favors BrCSC differentiation, converting a basal like phenotype into luminal. It induces the expression of a functional estrogen receptor (ER) and renders basal-like BrCSCs responsive to hormonal therapy. The key role played by miR-100 in breast cancer free-survival is confirmed by the analysis of a cohort of patients' tumors, which shows that low expression of miR-100 is a negative prognostic factor and is associated with gene signatures of high grade undifferentiated tumors. Our findings indicate a new possible therapeutic strategy, which could make aggressive breast cancers responsive to standard treatments.Oncotarget 12/2014; · 6.63 Impact Factor
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ABSTRACT: Triple-negative breast cancer is associated with poor prognosis because of a high rate of tumor recurrence and metastasis. Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24-/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24-/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation.PLoS ONE 09/2014; 9(9):e107616. · 3.53 Impact Factor
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ABSTRACT: We studied the correlation between epidermal growth factor receptor (EGFR) and the tumor stem cell markers CD44/CD24 in breast invasive ductal carcinoma (BIDC) and their relationship with prognosis. We analyzed the clinical data of 139 BIDC cases retrospectively, detecting EGFR, CD44, and CD24 expressions in tumor tissue using immunohistochemistry. The proportion of EGFR-, CD44-, and CD24-positive cases was 59.0, 62.3, and 30.9 %, respectively. The proportion of CD44-positive [76.9 % (p < 0.05)] and EGFR-positive [67.2 % (p = 0.108)] cases in the triple-negative breast cancer (TNBC) group was higher than that of the non-TNBC group. In the non-TNBC group, 36.5 % was CD24-positive, higher than that in the TNBC group but not statistically significant. The proportion of CD44-positive cases was significantly higher in the EGFR-positive group than in the EGFR-negative group (p = 0.017). EGFR-positive cases were significantly correlated with premenopausal status (p = 0.036), distant metastasis (p = 0.018), and estrogen receptor-negative status (p = 0.020). CD44-positive status was significantly correlated with human epidermal growth receptor 2 (HER2)-negative (p = 0.023), estrogen receptor-negative (p = 0.021), and progesterone receptor-negative status (p = 0.004). CD24-positive status was significantly correlated with HER2-positive status (p = 0.001). Kaplan-Meier survival analysis showed that TNBC patients had shorter survival. EGFR-positive and CD44-positive status were both correlated with shorter survival in the lymph node- and HR-negative groups, while CD24 positive was significantly correlated with poor survival in lymph node-negative and HR-positive patients. EGFR and CD44 expressions have a significantly positive correlation (p = 0.017) in BIDC. Patients both EGFR and CD44 positive had the worst outcome.Medical Oncology 01/2015; 32(1):275. · 2.06 Impact Factor