ERM/Rho protein expression in ductal breast cancer: a 15 year follow-up

Hałoń, Agnieszka; Donizy, Piotr; Surowiak, Paweł; Matkowski, Rafał

doi:10.1007/s13402-013-0125-9

Cited by 31 publications

(26 citation statements)

References 31 publications

(38 reference statements)

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“…In agreement with Halon et al [10], we show that a high proportion of cells in the BC tumor-stromal compartment were positive for RhoA and Rac1. In addition, we have shown that activated fibroblasts, as identified by α-SMA, were present in the majority of metastatic lymph node cases, whereas non-involved lymph nodes were devoid of myofibroblasts.…”

Section: Discussionsupporting

confidence: 93%

“…Rho proteins are involved in stress fiber formation and focal adhesion, while Rac proteins stimulate lamellipodia and membrane-ruffle formation [30][31][32][33]. Increasing evidence suggests that the RhoA and Rac1 proteins play an important role in cell migration, loss of adhesion, invasion, and metastasis in tumors [10,[34][35][36][37]. Building on these studies, we used immunohistochemistry to investigate whether the RhoA and Rac1 expression patterns were similar in fibroblasts of primary BC tumors and matched lymph node metastases.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the GTPase family members RhoA, RAC1, and RAC2, as well as collagens and integrins, which are known to mediate migration and invasiveness, were shown to be differentially regulated in the context of CAFs. To date, increased expression of these proteins, particularly within the epithelial compartment, has been shown to be important for cellular motility, loss of adhesion, invasion, and metastasis [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer

et al. 2015

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The importance of tumor-stromal cell interactions in breast tumor progression and invasion is well established. Here, an evaluation of differential genomic profiles of carcinoma-associated fibroblasts (CAFs) compared to fibroblasts derived from tissues adjacent to fibroadenomas (NAFs) revealed altered focal adhesion pathways. These data were validated through confocal assays. To verify the possible role of fibroblasts in lymph node invasion, we constructed a tissue microarray consisting of primary breast cancer samples and corresponding lymph node metastasis and compared the expression of adhesion markers RhoA and Rac1 in fibroblasts located at these different locations. Two distinct tissue microarrays were constructed from the stromal component of 43 primary tumors and matched lymph node samples, respectively. Fibroblasts were characterized for their expression of α-smooth muscle actin (α-SMA) and vimentin. Moreover, we verified the level of these proteins in the stromal compartment from normal adjacent tissue and in non-compromised lymph nodes. Our immunohistochemistry revealed that 59 % of fibroblasts associated with primary tumors and 41 % of the respective metastatic lymph nodes (p = 0.271) displayed positive staining for RhoA. In line with this, 57.1 % of fibroblasts associated with primary tumors presented Rac1-positive staining, and the frequency of co-positivity within the lymph nodes was 42.9 % (p = 0.16). Expression of RhoA and Rac1 was absent in fibroblasts of adjacent normal tissue and in compromised lymph nodes. Based on our findings that no significant changes were observed between primary and metastatic lymph nodes, we suggest that fibroblasts are active participants in the invasion of cancer cells to lymph nodes and support the hypothesis that metastatic tumor cells continue to depend on their microenvironment.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer

et al. 2015

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“…By this, the small GTPase RhoA is activated which induces the production of stress fibers and the up-regulation of the rhoA gene82. We found ITGB1 up-regulated in 4 h-AD-samples.…”

Section: Discussionmentioning

confidence: 69%

Identifications of novel mechanisms in breast cancer cells involving duct-like multicellular spheroid formation after exposure to the Random Positioning Machine

Kopp

Slumstrup

Corydon

et al. 2016

Sci Rep

102

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Many cell types form three-dimensional aggregates (MCS; multicellular spheroids), when they are cultured under microgravity. MCS often resemble the organ, from which the cells have been derived. In this study we investigated human MCF-7 breast cancer cells after a 2 h-, 4 h-, 16 h-, 24 h- and 5d-exposure to a Random Positioning Machine (RPM) simulating microgravity. At 24 h few small compact MCS were detectable, whereas after 5d many MCS were floating in the supernatant above the cells, remaining adherently (AD). The MCS resembled the ducts formed in vivo by human epithelial breast cells. In order to clarify the underlying mechanisms, we harvested MCS and AD cells separately from each RPM-culture and measured the expression of 29 selected genes with a known involvement in MCS formation. qPCR analyses indicated that cytoskeletal genes were unaltered in short-term samples. IL8, VEGFA, and FLT1 were upregulated in 2 h/4 h AD-cultures. The ACTB, TUBB, EZR, RDX, FN1, VEGFA, FLK1 Casp9, Casp3, PRKCA mRNAs were downregulated in 5d-MCS-samples. ESR1 was upregulated in AD, and PGR1 in both phenotypes after 5d. A pathway analysis revealed that the corresponding gene products are involved in organization and regulation of the cell shape, in cell tip formation and membrane to membrane docking.

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“…Moreover, the authors also confirmed that ezrin expression in this region was negatively correlated with overall survival and disease-free overall survival (101). Likewise, Halon et al reported that a large amount of ezrin-positive signals was observed in tumor tissue of breast cancer patients, based on immunohistochemical studies (102). Additionally, mRNA levels of radixin in brain tissue from patients with gliomas was significantly higher than those found in normal brain (103).…”

Section: Erm Proteinsmentioning

confidence: 61%

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

et al. 2014

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Abstract. In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.Keywords: P-glycoprotein, anticancer drug, drug-drug interaction, opioid, cancer *Corresponding author. stoku@pharm.Kobegakuin.ac.jp Published online in J-STAGE on July 2, 2014 doi: 10.1254/jphs.14R01CRInvited article 243 Changes in P-gp by Anticancer Treatment targeted anticancer drugs acting on specific genes or their products has grown rapidly. In fact, combination treatment with molecularly targeted drugs and cytotoxic chemotherapy against cancers such as acute leukemia or lymphatic malignancy improved therapeutic outcome in comparison to conventional anticancer chemotherapy (8, 9). However, solid tumors often have greater inherent resistance and are less sensitive to anticancer drugs (10). Furthermore, chronic exposure to anticancer drugs frequently leads to multi-drug resistance where the therapeutic effects of these drugs on tumors is largely reduced (11). The development of resistance to anticancer chemotherapy remains one of the major obstacles in effective pharmacological therapy for cancer using current treatment strategies (12).Research revealing the role of drug transporters in cancer began with the discovery of P-glycoprotein (P-gp). In 1976, during research to elucidate the mechanism by which cancer cell lines acquire multi-drug resistance, Juliano et al. discovered that P-gp is over-expressed on the surface membranes of multi-drug resistant cancer cells (13). Subsequent studies have demonstrated that P-gp is present in cancer tissue (11,14), as well as in normal tissues such as small intestine, where it regulates drug absorption, and liver and kidney, where it modulates drug clearance (15). These results suggest that P-gp determines blood levels of its substrate drugs. Furthermore, P-gp is now considered to be an extremely important factor in the pharmacokinetics of drugs bec...

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ERM/Rho protein expression in ductal breast cancer: a 15 year follow-up

Cited by 31 publications

References 31 publications

Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer

Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer

Identifications of novel mechanisms in breast cancer cells involving duct-like multicellular spheroid formation after exposure to the Random Positioning Machine

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

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