Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy

Li, Xiaoxian; Lewis, Michael T.; Huang, Jian; Gutiérrez, Carolina; Osborne, C. Kent; Wu, Meng; Hilsenbeck, Susan G.; Pavlick, Anne C.; Zhang, Xiaomei; Chamness, Gary C.; Wong, Helen; Rosen, Jeffrey M.; Chang, Jenny C.

doi:10.1093/jnci/djn123

Cited by 1,602 publications

(1,254 citation statements)

References 25 publications

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“…Our data are not consistent with the hypothesis that residual malignant disease after chemotherapy is enriched by a stem-like cell population with low proliferation that is associated with worse outcome [23]. However, a subpopulation of such stem-like cells may reside in the otherwise highly proliferative residual disease.…”

Section: Discussioncontrasting

confidence: 99%

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer

Jones

Salter

A’Hern

et al. 2008

Breast Cancer Res Treat

253

170

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Section: Discussioncontrasting

confidence: 99%

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer

Jones

Salter

A’Hern

et al. 2008

Breast Cancer Res Treat

253

170

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“…[47][48][49][50] Therefore, it is imperative to identify the mechanisms responsible for the survival and maintenance of CSC in order to design new therapeutic strategies targeting CSCs. Importantly, the non-CSCs display certain degree of plasticity to spontaneously dedifferentiate into CSC phenotype.…”

Section: Discussionmentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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“…33 With this property, cancer stem cells are thought to be more resistant to chemotherapeutic agents or radiotherapy. 34,35 Expression of stem cell markers in some tumors has been associated with adverse clinical outcomes. 16,[18][19][20][21][22][23] Cancer stem cells are also known to have an important role in the process of metastasis.…”

Section: Modern Pathology (2013) 26 1123-1131mentioning

confidence: 99%

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

et al. 2013

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Colorectal micropapillary carcinoma has recently been reported as an aggressive variant of adenocarcinoma with a high incidence of lymph node metastasis, but has not been well investigated in terms of survival analysis. This study analyzed the clinicopathological characteristics, including survival data, of the patients with micropapillary carcinoma. We hypothesized that the aggressive features of micropapillary carcinoma might be related to the presence of more tumor cells with stem cell phenotype in colorectal cancer. Fifty-five (10%) micropapillary carcinoma cases were identified among 561 cases of colorectal cancer. We compared the clinicopathological characteristics, including survival data and immunohistochemical profiles of stem cell markers (SOX2, NOTCH3, CD44v6, CD166, ALDH1) of micropapillary carcinomas with those of randomly selected 112 conventional adenocarcinomas lacking micropapillary carcinoma components (non-micropapillary carcinoma) in the colorectum. To exclude the possibility of dilution of control group by patients with microsatellite instability-high carcinomas, we divided non-micropapillary carcinomas into microsatellite instability-high carcinoma and microsatellite stable tumors. Micropapillary carcinomas were characterized by more frequent lymphovascular invasion (Po0.0001) and lymph node metastasis (Po0.0001), higher pathological T and tumor node metastasis stages (P ¼ 0.047 and P ¼ 0.001), and more frequent SOX2 (P ¼ 0.038) and NOTCH3 expressions (P ¼ 0.005). Overall 5-year survival rate for patients with micropapillary carcinoma (37%) was significantly lower than for microsatellite instability-high carcinoma and microsatellite stable carcinoma patients (92 and 72%, Po0.0001). The presence of the micropapillary carcinoma component was shown to be associated with a significantly worse survival rate in univariate (Po0.0001) and multivariate (P ¼ 0.003, Cox hazard ratio 2.402) analyses. In conclusion, recognition of the micropapillary carcinoma component in colonic adenocarcinoma is very important, because the micropapillary carcinoma has been associated with a significantly worse prognosis. We also found a higher expression rate of cancer stem cell markers in micropapillary carcinomas, suggesting their potential contribution to the survival disadvantage of micropapillary carcinoma. Modern Pathology (2013Pathology ( ) 26, 1123Pathology ( -1131 doi:10.1038/modpathol.2012 published online 12 October 2012 Keywords: colorectum; micropapillary carcinoma; prognosis; stem cell marker; TNM stage Colorectal cancer is one of the leading causes of cancer deaths worldwide, and both the prevalence and the incidence rate in South Korea are rapidly rising. 1 For metastatic colorectal cancer, the 5-year survival rate is only about 10%. 2 Micropapillary carcinoma is a relatively uncommon and distinctive tumor characterized by small clusters of tumor cells in the clear lacunar spaces, mimicking lymphatic or vascular channels. 3 Micropapillary carcinoma has high potential to metastasize to the regional l...

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Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy

Cited by 1,602 publications

References 25 publications

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

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