Expression of cancer stem cell markers in basal and penta-negative breast carcinomas – A study of a series of triple-negative tumors

Uchôa, Diego de Mendonça; Graudenz, Márcia Silveira; Callegari-Jacques, Sídia M.; Hartmann, Carolina Rigatti; Pellini, Bruna; Fitarelli-Kiehl, Mariana; Edelweiss, Maria Isabel Albano

doi:10.1016/j.prp.2014.03.005

Cited by 13 publications

(4 citation statements)

References 60 publications

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“…Among the CD44/CD24 phenotypes, CD44 + CD24 -/low has been associated with more aggressive TNBC regarding the tumor size, TMN stage, and lymph node metastasis (29). Consistent with this, the CD44 -/CD24 + phenotype has associated with less lymphovascular invasion in TNBC patients (32). Besides, the CD44 + CD24 -/low phenotype has been more frequent in high-grade TNBC cells (33).…”

Section: The Cd44 + Cd24 -/Low Phenotype and Its Association With Clinicopathological Features Of Tnbc Patientssupporting

confidence: 64%

“…The expression of CD44 has been substantially associated with higher tumor grade, lymph node metastasis, and advanced tumor stage in TNBC patients ( 29 ). Consistent with this, CD44 has been implicated in promoting lymphovascular invasion in TNBC patients ( 32 ). In line with this, there has been a remarkable association between CD44 expression and tumor metastasis in TNBC patients ( 25 ).…”

Section: Discussionmentioning

confidence: 60%

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A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

et al. 2021

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As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44+CD24-/low as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44+CD24-/low phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44+CD24-/low phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44+CD24-/low phenotype can be utilized to determine TNBC patients’ prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.

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Section: The Cd44 + Cd24 -/Low Phenotype and Its Association With Clinicopathological Features Of Tnbc Patientssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 60%

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

et al. 2021

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“…However, we did not find any association with the clinical features including age, tumor size, lymph node status, histological grade, TNM stage and Ki-67. The discordance may ascribe to the different subtypes of breast cancer we studied, as some recent reports have not yet shown any association with the clinicopathologic variables in TNBC 28, 33. There are limited data indicating the prognostic role of CD44 + /CD24 - phenotype in TNBC.…”

Section: Discussionmentioning

confidence: 80%

Evaluation of Breast Cancer Stem Cells and Intratumor Stemness Heterogeneity in Triple-negative Breast Cancer as Prognostic Factors

Yang¹,

Cao²,

Sun³

et al. 2016

Int. J. Biol. Sci.

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Triple-negative breast cancer (TNBC) is a tumor subtype with aggressive behavior and poor clinical outcome for lacking effective therapies. Breast cancer stem cells (BCSCs) have been suggested to have tumor-initiating properties, but it remains unclear whether their presence contributes to the increased aggressiveness and poor prognosis of TNBC. Also, the breast cancers display frequent inter- and intra-tumor heterogeneity, which adds the complexity in diagnosis and predicting prognosis. Here we investigated the clinical relevance and prognostic value of the BCSC markers, CD44+/CD24-, aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and CD133 in 88 TNBC cases. We found that a few patients displayed spatial heterogeneity of the BCSC markers in expression, which was defined as intratumor stemness heterogeneity (ITSH) below. There was no significant correlation between any BCSC marker alone or ITSH and progression-free survival (PFS). Interestingly, the combined BCSC phenotype by CD44+/CD24- and ALDH1A1 was significantly associated with worse PFS (P = 0.009). Further stratification analysis revealed that this combined BCSC phenotype was an independent prognostic factor for PFS in some subgroups. In conclusion, we demonstrated the existence of ITSH in TNBC and found that the ITSH as well as a single BCSC marker was not significantly associated with survival, whereas combing the analysis of BCSC markers could improve prognostic value. Our findings may lead to an improvement of prognostic indicators in TNBC.

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“…TNBCs are highly heterogeneous tumors characterized by the lack of expression of estrogen, progesterone, and human epidermal growth factor receptor-2 (HER2) receptors (Dent, et al 2007; Foulkes, et al 2010). In many advanced cancers, including TNBC, cancer cells are hierarchically organized with a subpopulation of multipotent, self-renewing cells at the apex termed cancer stem cells (CSCs) (Idowu, et al 2012; Uchoa Dde, et al 2014; Zheng, et al 2013). CSCs possess an enhanced ability to initiate and induce tumorigenesis and express the embryonic stem cell transcription factors NANOG, SOX2, and OCT4 (Al-Hajj, et al 2003; Collins, et al 2005; Lathia, et al 2015; Ohi, et al 2011).…”

Section: Introductionmentioning

confidence: 99%

STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance

Thiagarajan¹,

Zheng²,

Bhagrath³

et al. 2017

Endocrine-Related Cancer

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Leptin (LEP) binds to the long form of the leptin receptor (LEPRb), leading to activation of multiple signaling pathways that are potential targets for disrupting the obesity-breast cancer link. In triple-negative breast cancer (TNBC), LEP is hypothesized to predominantly mediate its tumorigenic effects via a subpopulation of LEPRb-positive tumor cells termed cancer stem cells (CSCs) that can initiate tumors and induce tumor progression. Previously, we showed that LEP promotes CSC survival in vivo. Moreover, silencing LEPRb in TNBC cells compromised the CSC state. The mechanisms by which LEPRb regulates TNBC CSC intracellular signaling are not clear. We hypothesized that activation of LEPRb signaling is sufficient to drive CSC maintenance in TNBC. Here, we show that activation of LEPRb in non-CSCs isolated using our CSC reporter system resulted in a transition to the stem cell state. In CSCs, LEP induced STAT3 phosphorylation, whereas LEP did not induce STAT3 phosphorylation in non-CSCs. Introduction of constitutively active STAT3 into LEPRb-transfected non-CSCs significantly induced NANOG, SOX2, and OCT4 expression compared with control non-CSCs. To determine the intracellular phospho-tyrosine residue of LEPRb that is necessary for the induction of the stem cell state in non-CSCs, we transfected the tyrosine residue point mutants L985, F1077, and S1138 into non-CSCs. Non-CSCs transfected with the L985 mutant exhibited increased STAT3 phosphorylation, increased SOCS3 expression, and an induction of GFP expression compared with non-CSCs expressing the F1077 and S1138 mutants. Our data demonstrate that LEPRb-induced STAT3 activation is essential for the induction and maintenance of TNBC CSCs.

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Expression of cancer stem cell markers in basal and penta-negative breast carcinomas – A study of a series of triple-negative tumors

Cited by 13 publications

References 60 publications

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

Evaluation of Breast Cancer Stem Cells and Intratumor Stemness Heterogeneity in Triple-negative Breast Cancer as Prognostic Factors

STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance

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