Loss of sphingosine kinase 1 increases lung metastases in the MMTV-PyMT mouse model of breast cancer

Breast cancer is a very heterogeneous disease, and ~30% of breast cancer patients succumb to metastasis, highlighting the need to understand the mechanisms of breast cancer progression in order to identify new molecular targets for treatment. Sphingosine kinase 1 (SK1) has been shown to be upregulated in patients with breast cancer, and several studies have suggested its involvement in breast cancer progression and/or metastasis, mostly based on cell studies. In this work we evaluated the role of SK1 in breast cancer development and metastasis using a transgenic breast cancer model, mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT), that closely resembles the characteristics and evolution of human breast cancer. The results show that SK1 deficiency does not alter tumor latency or growth, but significantly increases the number of metastatic lung nodules and the average metastasis size in the lung of MMTV-PyMT mice. Additionally, analysis of Kaplan-Meier plotter of human disease shows that high SK1 mRNA expression can be associated with a better prognosis for breast cancer patients. These results suggest a metastasis-suppressing function for SK1 in the MMTV-PyMT model of breast cancer, and that its role in regulating human breast cancer progression and metastasis may be dependent on the breast cancer type.

Download Full-text

A New Invasion and Metastasis Molecule, Tiaml and Its Interaction With the Cytoskeleton Are Involved in Human Breast Cancer Progression

10.21236/ada392244 ◽

2000 ◽

Author(s):

Lilly Y. Bourguignon

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Human Breast Cancer ◽

Breast Cancer Progression ◽

Human Breast ◽

Invasion And Metastasis

Download Full-text

Antiestrogen-resistant human breast cancer cells require activated Protein Kinase B/Akt for growth

Endocrine Related Cancer ◽

10.1677/erc.1.00946 ◽

2005 ◽

Vol 12 (3) ◽

pp. 599-614 ◽

Cited By ~ 57

Author(s):

T Frogne ◽

J S Jepsen ◽

S S Larsen ◽

C K Fog ◽

B L Brockdorff ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cell Lines ◽

Human Breast Cancer ◽

Neutralizing Antibodies ◽

Breast Cancer Cells ◽

Resistant Cell ◽

Breast Cancer Patients ◽

Human Breast ◽

Mcf 7

Development of acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. The IGF system plays a profound role in many cancer types, including breast cancer. Thus, overexpression and/or constitutive activation of the IGF-I receptor (IGF-IR) or different components of the IGF-IR signaling pathway have been reported to render breast cancer cells less estrogen dependent and capable of sustaining cell proliferation in the presence of antiestrogens. In this study, growth of the antiestrogen-sensitive human breast cancer cell line MCF-7 was inhibited by treatment with IGF-IR-neutralizing antibodies. In contrast, IGF-IR-neutralizing antibodies had no effect on growth of two different antiestrogen-resistant MCF-7 sublines. A panel of antiestrogen-resistant cell lines was investigated for expression of IGF-IR and either undetectable or severely reduced IGF-IR levels were observed. No increase in insulin receptor substrate 1 (IRS-1) or total PKB/Akt (Akt) was detected in the resistant cell lines. However, a significant increase in phosphorylated Akt (pAkt) was found in four of six antiestrogen-resistant cell lines. Overexpression of pAkt was associated with increased Akt kinase activity in both a tamoxifen- and an ICI 182,780-resistant cell line. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin or the Akt inhibitor SH-6 (structurally modified phosphatidyl inositol ether liquid analog PIA 6) resulted in a more pronounced growth inhibitory effect on the antiestrogen-resistant cells compared with the parental cells, suggesting that signaling via Akt is required for antiestrogen-resistant cell growth in at least a subset of our antiestrogen-resistant cell lines. PTEN expression and activity was not decreased in cell lines overexpressing pAkt. Our data demonstrate that Akt is a target for treatment of antiestrogen-resistant breast cancer cell lines and we suggest that antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit Akt signaling.

Download Full-text

Proteomic Portrait of Human Breast Cancer Progression Identifies Novel Prognostic Markers

Cancer Research ◽

10.1158/0008-5472.can-11-3711 ◽

2012 ◽

Vol 72 (9) ◽

pp. 2428-2439 ◽

Cited By ~ 88

Author(s):

Tamar Geiger ◽

Stephen F. Madden ◽

William M. Gallagher ◽

Juergen Cox ◽

Matthias Mann

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Human Breast Cancer ◽

Prognostic Markers ◽

Breast Cancer Progression ◽

Human Breast

Download Full-text

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

Cancers ◽

10.3390/cancers12010029 ◽

2019 ◽

Vol 12 (1) ◽

pp. 29 ◽

Cited By ~ 3

Author(s):

Jyun-Yuan Huang ◽

Yen-Yun Wang ◽

Steven Lo ◽

Ling-Ming Tseng ◽

Dar-Ren Chen ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Progression ◽

Human Breast Cancer ◽

Breast Cancer Progression ◽

Akt Pathway ◽

Adipose Derived Stem Cells ◽

Human Breast ◽

Akt Inhibitor ◽

Promoting Effect

Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression.

Download Full-text

Downregulation of the Novel Candidate Tumor Suppressor Gene NCOR2/SMRT in Human Breast Cancer Progression.

10.1158/0008-5472.sabcs-09-3150 ◽

2009 ◽

Author(s):

J. Geradts ◽

R. Saxena ◽

J. Groth ◽

M. Desouki ◽

J. Burchette ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Cancer Progression ◽

Human Breast Cancer ◽

Suppressor Gene ◽

Breast Cancer Progression ◽

The Novel ◽

Human Breast ◽

Candidate Tumor Suppressor Gene

Download Full-text

The role of microRNAs in human breast cancer progression

Tumor Biology ◽

10.1007/s13277-014-2202-8 ◽

2014 ◽

Vol 35 (7) ◽

pp. 6235-6244 ◽

Cited By ~ 38

Author(s):

WenCheng Zhang ◽

Jinbo Liu ◽

Guangshun Wang

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Human Breast Cancer ◽

Breast Cancer Progression ◽

Human Breast

Download Full-text

Selective Cox-2 inhibition attenuates the perioperative increase of the tumour enhancing pro-angiogenic cytokine Vegf in human breast cancer patients

Journal of Surgical Research ◽

10.1016/j.jss.2003.08.140 ◽

2003 ◽

Vol 114 (2) ◽

pp. 243 ◽

Cited By ~ 2

Author(s):

G.T. O’Donoghue ◽

G. Roche-Nagle ◽

E.M. Connolly ◽

J. Harmey ◽

D.J. Bouchier-Hayes

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Human Breast Cancer ◽

Breast Cancer Patients ◽

Human Breast ◽

Cox 2

Download Full-text

The Hedgehog signalling pathway mediates drug response of MCF-7 mammosphere cells in breast cancer patients

Clinical Science ◽

10.1042/cs20140592 ◽

2015 ◽

Vol 129 (9) ◽

pp. 809-822 ◽

Cited By ~ 24

Author(s):

Miao He ◽

Yingzi Fu ◽

Yuanyuan Yan ◽

Qinghuan Xiao ◽

Huizhe Wu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Human Breast Cancer ◽

Drug Response ◽

Breast Cancer Patients ◽

Human Breast ◽

Hedgehog Signalling ◽

Hedgehog Signalling Pathway ◽

Xenograft Mice ◽

Mcf 7

Our study showed that Hh signalling activation contributed to BCSC-mediated chemoresistance in cultured breast cancer MCF-7 MS cells, in xenograft mice and in human breast cancer patients.

Download Full-text