Role of Sphk1 in the malignant transformation of breast epithelial cells and breast cancer progression

Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and epigenetic changes in cell cycle regulatory genes and other genes which regulate the cell cycle. This suggests that multiple, distinct pathways of genetic alterations lead to cancer development. Products of both oncogenes (including cyclin-dependent kinase (CDKs) and cyclins) and tumor suppressor genes (including cyclin-dependent kinase inhibitors) regulate cell cycle machinery and promote or suppress cell cycle progression, respectively. The identification of cyclins and CDKs help to explain and understand the molecular mechanisms of cell cycle machinery. During breast cancer tumorigenesis, cyclins A, B, C, D1, and E; cyclin-dependent kinase (CDKs); and CDK-inhibitor proteins p16, p21, p27, and p53 are known to play significant roles in cell cycle control and are tightly regulated in normal breast epithelial cells. Following mitogenic stimuli, these components are deregulated, which promotes neoplastic transformation of breast epithelial cells. Multiple studies implicate the roles of both types of components—oncogenic CDKs and cyclins, along with tumor-suppressing cyclin-dependent inhibitors—in breast cancer initiation and progression. Numerous clinical studies have confirmed that there is a prognostic significance for screening for these described components, regarding patient outcomes and their responses to therapy. The aim of this review article is to summarize the roles of oncogenic and tumor-suppressive components of the cell cycle in breast cancer progression and prognosis.

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Role of the Microenvironment in Regulating Normal and Cancer Stem Cell Activity: Implications for Breast Cancer Progression and Therapy Response

Cancers ◽

10.3390/cancers11091240 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1240 ◽

Cited By ~ 10

Author(s):

Vasudeva Bhat ◽

Alison L. Allan ◽

Afshin Raouf

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Epithelial Cells ◽

Cancer Stem Cells ◽

Breast Tissue ◽

Therapy Response ◽

Breast Epithelial Cells ◽

Tissue Microenvironment ◽

Breast Epithelial

The epithelial cells in an adult woman’s breast tissue are continuously replaced throughout their reproductive life during pregnancy and estrus cycles. Such extensive epithelial cell turnover is governed by the primitive mammary stem cells (MaSCs) that proliferate and differentiate into bipotential and lineage-restricted progenitors that ultimately generate the mature breast epithelial cells. These cellular processes are orchestrated by tightly-regulated paracrine signals and crosstalk between breast epithelial cells and their tissue microenvironment. However, current evidence suggests that alterations to the communication between MaSCs, epithelial progenitors and their microenvironment plays an important role in breast carcinogenesis. In this article, we review the current knowledge regarding the role of the breast tissue microenvironment in regulating the special functions of normal and cancer stem cells. Understanding the crosstalk between MaSCs and their microenvironment will provide new insights into how an altered breast tissue microenvironment could contribute to breast cancer development, progression and therapy response and the implications of this for the development of novel therapeutic strategies to target cancer stem cells.

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NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways

10.21203/rs.2.24259/v2 ◽

2020 ◽

Author(s):

Lin Cao ◽

Xin Wang ◽

Juhong Yang ◽

Jia Guo ◽

Xiang Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Adhesion ◽

Epithelial Cells ◽

Signaling Pathway ◽

Functional Role ◽

Polysialic Acid ◽

Breast Epithelial Cells ◽

Differential Signaling ◽

Breast Epithelial

Abstract Background Neural cell adhesion molecule (NCAM), a common mammalian cell surface glycoprotein, is the major substrate of polysialic acid (polySia). Polysialylated NCAM occurs in many types of cancer, but rarely in normal adult tissues. Epithelial-mesenchymal transition (EMT) is an important process contributing to tumor metastasis. The functional role of NCAM hypersialylation in EMT is unclear. Method Expression of NCAM and polysialylated NCAM in breast cancer progression were evaluated by western blot (WB), immunohistochemistry, semi-quantitative PCR and immunoprecipitation (IP). Overexpression of NCAM-140 and ST8SiaII were performed to assess the functional role of NCAM hypersialylation by liposome transfection. Cell proliferation ability was investigated with MTT assay. Transwell and wound closure assay were conducted to evaluate cell migratory ability. Phagokinetic gold sol assay and cell adhesion assay were performed to assess cell motility ability and cell adhesion ability, respectively. Furthermore, WB and IP were used to reveal the activated signaling pathway. Results The present study indicates that NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways, based on the following observations: (i) NCAM and polysialylated NCAM were aberrantly regulated in breast cancer cells; (ii) NCAM and polysialylated NCAM expression were upregulated in normal breast epithelial cells undergoing EMT; (iii) NCAM overexpression induced EMT in breast epithelial cells; (iv) NCAM promoted cell proliferation and migration through activation of a β-catenin/slug signaling pathway; (v) modification of polySia attached to NCAM inhibited cell adhesion and promoted cell motility through activation of an EGFR/STAT3 pathway. Conclusion This study demonstrates that NCAM and polysialylated NCAM facilitate different signaling pathway and affect different cell behaviors. Switching between the NCAM-mediated pathways appeared to depend on polySia decoration.

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Endotoxin Triggers Tumor Initiation Events in Nontumorigenic Breast Epithelial Cells and Enhances Invasion-Related Phenotype in Pretumorigenic and Tumorigenic Breast Epithelial Cells

International Journal of Inflammation ◽

10.1155/2021/4666380 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Farah Yassine ◽

Sabreen F. Fostok ◽

Nataly Naser Al Deen ◽

Rabih S. Talhouk

Keyword(s):

Breast Cancer ◽

Epithelial Cells ◽

Human Breast ◽

Short Term ◽

Breast Epithelial Cells ◽

Inflammatory Phenotype ◽

Breast Cells ◽

Breast Epithelial

Inflammation is associated with the development of several cancers, including breast cancer. However, the molecular mechanisms driving breast cancer initiation or enhancement by inflammation are yet to be deciphered. Hence, we opted to investigate the role of inflammation in initiating and enhancing tumor-like phenotypes in nontumorigenic, pretumorigenic, and tumorigenic breast epithelial cells. Noncytotoxic endotoxin (ET) concentrations capable of inducing an inflammatory phenotype were determined for the different cell lines. Results showed that short-term ET exposure upregulated matrix metalloproteinase-9 (MMP-9) activity in nontumorigenic mammary epithelial cells of mouse (SCp2) and human origins (HMT-3522 S1; S1) and upregulated inflammatory mediators including nitric oxide (NO) and interleukin 1-β in tumorigenic human breast cells (MDA-MB-231), all in a dose-dependent manner. Long-term ET treatment, but not short-term, triggered the migration of SCp2 cells, and proliferation and migration of tumorigenic human breast cells MCF-7 and MDA-MB-231. Both short- and long-term ET exposures preferentially enhanced the invasion of pretumorigenic S1-connexin 43 knockout (Cx43-KO S1) cells compared to their nontumorigenic S1 counterparts. Moreover, both ET exposures disrupted lumen formation and apicolateral distribution of β-catenin in 3D cultures of S1 cells. In conclusion, ET treatment at concentrations that elicited inflammatory phenotype triggered tumor initiation events in nontumorigenic and pretumorigenic breast cells, and increased tumorigenicity of breast cancer cells. Our findings highlight the role of inflammation in enhancing migration, invasion, and loss of normal 3D morphology and suggest that such inflammatory insults can “add injury” to pretumorigenic and tumorigenic breast epithelial cells.

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NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways

10.21203/rs.2.24259/v1 ◽

2020 ◽

Author(s):

Lin Cao ◽

Xin Wang ◽

Juhong Yang ◽

Jia Guo ◽

Xiang Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cell Adhesion ◽

Epithelial Cells ◽

Functional Role ◽

Polysialic Acid ◽

Breast Epithelial Cells ◽

Differential Signaling ◽

Breast Epithelial

Abstract Background Neural cell adhesion molecule (NCAM), a common mammalian cell surface glycoprotein, is the major substrate of polysialic acid (PSA). Polysialylated NCAM occurs in many types of cancer, but rarely in normal adult tissues. Epithelial-mesenchymal transition (EMT) is an important process contributing to tumor metastasis. The functional role of NCAM hypersialylation in EMT is unclear. Method Expression of NCAM and PSA-NCAM in breast cancer progression were evaluated by western blot (WB), immunohistochemistry, semi-quantitative PCR and immunoprecipitation (IP). Overexpression of NCAM-140 and STX were performed to assess the functional role of NCAM hypersialylation by liposome transfection. Then, the cell proliferation ability was investigated with MTT assay. Transwell and wound closure assay were conducted to evaluate cell migratory ability. Phagokinetic gold sol assay and cell adhesion assay were performed to assess cell motility ability and cell adhesion ability, respectively. Furthermore, WB and IP were used to reveal the activated signaling pathway. Results The present study indicates that NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways, based on the following observations: (i) NCAM and PSA-NCAM were aberrantly regulated in breast cancer cells; (ii) NCAM and PSA-NCAM expression were upregulated in normal breast epithelial cells undergoing EMT; (iii) NCAM overexpression induced EMT in breast epithelial cells; (iv) NCAM promoted cell proliferation and migration through activation of a β-catenin/slug signaling pathway; (v) modification of PSA attached to NCAM inhibited cell adhesion and promoted cell motility through activation of an EGFR/STAT3 pathway. Conclusion These observations help clarify the molecular mechanisms whereby PSA and its major substrate NCAM modulate cell behaviors, and the significance of increased PSA expression on NCAM during EMT and tumor development.

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NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways

10.21203/rs.2.24259/v3 ◽

2020 ◽

Author(s):

Lin Cao ◽

Xin Wang ◽

Juhong Yang ◽

Jia Guo ◽

Xiang Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Adhesion ◽

Epithelial Cells ◽

Signaling Pathway ◽

Functional Role ◽

Polysialic Acid ◽

Breast Epithelial Cells ◽

Differential Signaling ◽

Breast Epithelial

Abstract Background Neural cell adhesion molecule (NCAM), a common mammalian cell surface glycoprotein, is the major substrate of polysialic acid (polySia). Polysialylated NCAM occurs in many types of cancer, but rarely in normal adult tissues. Epithelial-mesenchymal transition (EMT) is an important process contributing to tumor metastasis. The functional role of NCAM hypersialylation in EMT is unclear. Method Expression of NCAM and polysialylated NCAM in breast cancer progression were evaluated by western blot (WB), immunohistochemistry, semi-quantitative PCR and immunoprecipitation (IP). Overexpression of NCAM-140 and ST8SiaII were performed to assess the functional role of NCAM hypersialylation by liposome transfection. Cell proliferation ability was investigated with MTT assay. Transwell and wound closure assay were conducted to evaluate cell migratory ability. Phagokinetic gold sol assay and cell adhesion assay were performed to assess cell motility ability and cell adhesion ability, respectively. Furthermore, WB and IP were used to reveal the activated signaling pathway. Results The present study indicates that NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways, based on the following observations: (i) NCAM and polysialylated NCAM were aberrantly regulated in breast cancer cells; (ii) NCAM and polysialylated NCAM expression were upregulated in normal breast epithelial cells undergoing EMT; (iii) NCAM overexpression induced EMT in breast epithelial cells; (iv) NCAM promoted cell proliferation and migration through activation of a β-catenin/slug signaling pathway; (v) modification of polySia attached to NCAM inhibited cell adhesion and promoted cell motility through activation of an EGFR/STAT3 pathway.Conclusion This study demonstrates that NCAM and polysialylated NCAM facilitate different signaling pathway and affect different cell behaviors. Switching between the NCAM-mediated pathways appeared to depend on polySia decoration.

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