New Findings on Breast Cancer Stem Cells: A Review

Bozorgi, Azam; Khazaei, Mohamad

doi:10.4048/jbc.2015.18.4.303

Cited by 102 publications

(71 citation statements)

References 131 publications

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“…To further investigate the effect of vitamin D compounds on cancer stem-like cells in TNBC, we analyzed SUM159 mammospheres treated with vitamin D compounds for expression of pluripotency and stem cell genes which have been shown to be important in breast cancer progression (19). The pluripotency marker, OCT4, was greatly reduced by treatment with 100 nM 1α,25(OH) 2 D 3 (29%, p <0.01) and 10 nM BXL0124 (39%, p <0.05) (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

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Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Shan

Wahler

Lee

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH)2D3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH)2D3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest that vitamin D compounds may serve as potential preventive agents to inhibit triple negative breast cancer by regulating cancer stem cells and differentiation.

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Section: Resultsmentioning

confidence: 99%

“…(A) qPCR analysis was performed on primary mammospheres harvested after five days of growth to assess the gene expression of Oct4, CD44, LAMA5 and NF-κB. Average Ct values are shown in parenthesis for OCT4 (22), CD44 (19), LAMA5 (22), and NF-κB (23). The experiments were repeated three times.…”

Section: Figurementioning

confidence: 99%

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Shan

Wahler

Lee

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…For example, recent work revealed that low CD24 surface expression leads to only a ~50% decrease in metastatic cancer burden while shRNA mediated silencing of CD24 results in a 90% decrease (9). In addition, ourselves (9) and others (17) have shown that cancer cells with little to no surface CD24 (surCD24-) retain significant tumorigenic properties. Together, these data suggest that CD24 exists in additional cellular locations and has significant biological activity.…”

Section: Introductionmentioning

confidence: 99%

Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis

Duex¹,

Owens²,

Chauca-Diaz³

et al. 2017

Cancer Research

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Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24-) still retain aggressive phenotypes in vitro and in vivo. Here we resolve this apparent paradox with the discovery of biologically active, nuclear CD24 (nucCD24) and finding that its levels are unchanged in surCD24- cells. Using the complementary techniques of biochemical cellular fractionation and immunofluorescence, we demonstrate a signal for CD24 in the nucleus in cells from various histological types of cancer. Nuclear-specific expression of CD24 (NLS-CD24) increased anchorage independent growth in vitro and tumor formation in vivo. Immunohistochemistry of patient tumor samples revealed the presence of nucCD24, whose signal intensity correlated positively with the presence of metastatic disease. Analysis of gene expression between cells expressing CD24 and NLS-CD24 revealed a unique nucCD24 transcriptional signature. The median score derived from this signature was able to stratify overall survival in 4 patient datasets from bladder cancer and 5 patient datasets from colorectal cancer. Patients with high scores (more nucCD24-like) had reduced survival. These findings define a novel and functionally important intracellular location of CD24, they explain why surCD24- cells can remain aggressive, and they highlight the need to consider nucCD24 in both fundamental research and therapeutic development.

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“…Interestingly, overexpression of GRP78 in both breast cancer cell lines caused an induction of the TIC subpopulation (i.e. CD24 -/CD44 + cells) [26] ( Figures 3A and 3B). Overexpressing GRP78 also induced the expression of aldehyde dehydrogenase 1 (ALDH1A), a marker associated with stemness and cancer [27] (Supplementary Figure S4).…”

Section: Resultsmentioning

confidence: 96%

“…Although sGRP78 shared similar functions on stem cells and cancer cells, whether or not sGRP78 expression was marking and/or affecting a stem-like subpopulation within breast cancer remained unclear. To begin to analyze the potential role of sGRP78 expression in stemness in cancer, we performed experiments with the breast cancer cell lines MCF7 (luminal A subtype [25]) and MDA-MB-231 (basal subtype [25]) that contain low or high levels of previously defined CD24 -/CD44 + tumor initiating cells (TICs) respectively, a cell population with breast cancer cells shown to be able to generate tumors with much higher efficiency in in vivo xenograft transplantation assays [26]. Interestingly, overexpression of GRP78 in both breast cancer cell lines caused an induction of the TIC subpopulation (i.e.…”

Section: Resultsmentioning

confidence: 99%

GRP78 promotes stemness in normal and neoplastic cells

Conner

Lager

Guldner

et al. 2019

Preprint

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Reliable approaches to identify stem cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how to best identify and target stem-like mechanisms aberrantly acquired by cancer cells has been challenging. We harnessed the power of reprogramming to examine GRP78, a chaperone protein generally restricted to the endoplasmic reticulum in normal tissues, but which is expressed on the cell surface of human embryonic stem cells and many cancer types. We have discovered that (1) cell surface GRP78 (sGRP78) is expressed on iPSCs and is important in reprogramming, (2) sGRP78 promotes cellular functions in both pluripotent and breast cancer cells (3) overexpression of GRP78 in breast cancer cells leads to an induction of a CD24 -/CD44 + tumor initiating cell (TIC) population (4) sGRP78 + breast cancer cells are enriched for stemness genes and appear to be a subset of TICs (5) sGRP78 + breast cancer cells show an enhanced ability to seed metastatic organ sites in vivo. These collective findings show that GRP78 has important functions in regulating both pluripotency and oncogenesis, and suggest that sGRP78 marks a stem-like population in breast cancer cells that has increased metastatic potential in vivo.

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New Findings on Breast Cancer Stem Cells: A Review

Cited by 102 publications

References 131 publications

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis

GRP78 promotes stemness in normal and neoplastic cells

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