Close

You Might Also Like

1 thought on “What is egfr in breast cancer”

Leave a Reply

Your email address will not be published. Required fields are marked *


For many years it was believed that EGFR plays a minor role in the development and progression of breast malignancies. However, recent findings have led investigators to revisit these beliefs. Here we will review these findings and propose roles that EGFR may play in breast malignancies. In particular, we will discuss the potential roles that EGFR may play in triple-negative tumors, resistance to endocrine therapies, maintenance of stem-like tumor cells, and bone metastasis.

Thus, we will propose the contexts in which EGFR may be a therapeutic target. The study of breast cancer has provided opportunities to test concepts emerging from basic studies of cell proliferation, signal transduction and developmental biology. One subject of these basic studies is the epidermal growth factor receptor EGFR or ErbB family of receptor tyrosine kinases.

These receptors play distinct roles in breast malignancies [ 1 — 15 ]. ErbB2 is a therapeutic target in breast tumors that overexpress the receptor. In contrast, the roles that ErbB4 plays in breast malignancies remain a subject of opposing views. EGFR signaling is stimulated by members of the epidermal growth factor EGF family of peptide growth factors, whose roles in stimulating ErbB receptor signaling and coupling to biological responses have been intensively studied [ 2121617 ].

These agonists are expressed as integral membrane proteins and are cleaved by metalloproteinases to release soluble, mature ligands. These metalloproteinases are typically members of the ADAM a disintegrin and metalloproteinase family of membraneous proteases. Because cleavage of the ligand precursors is required for release of soluble, mature ligands, ligand cleavage represents a potential point in which agonist-induced EGFR signaling can be regulated. However, the transmembrane ligands stimulate EGFR signaling on adjacent cells, apparently through a juxtracrine signaling mechanism What is egfr in breast cancer may mediate the stromal-epithelial interactions characteristic of the breast [ 23 — 25 ].

The mechanisms by which EGFR signaling is stimulated by agonist binding have been extensively studied [ 16172627 ]. To summarize, EGFR consists of an extracellular domain, a hydrophobic transmembrane domain, an intracellular catalytic tyrosine kinase domain, and several intracellular What is egfr in breast cancer residues whose phosphorylation is responsible for coupling to downstream effectors.

Ligand binding to the extracellular domain stabilizes the EGFR in an extended conformation that is competent for receptor dimerization. Dimerization then enables the cytoplasmic What is egfr in breast cancer of one receptor monomer the regulatory monomer to stabilize the tyrosine kinase domain of another monomer the catalytic monomer in the active conformation and presents the tyrosine residues of the regulatory monomer to the catalytic site of the catalytic monomer.

In this manner EGFR dimerization enables its tyrosine phosphorylation. Approximately 10 EGFR tyrosine residues are phosphorylated following ligand engagement and receptor dimerization Kristen stewart nude fakes bondage 1728 ]. These phosphorylation sites bind adapter proteins and other signaling molecules that possess SH2 Src-homology domain 2 or PTB phospho-tyrosine binding motifs.

Several of phosphorylated tyrosine residues can bind unique effectors and each EGFR agonist is likely to stimulate EGFR phosphorylation at a unique subset of tyrosine residues. These effectors are typically coupled to increased survival, proliferation, motility and invasiveness displayed by malignant tumor cells. In contrast, some EGFR agonists also stimulate coupling to downstream molecules that negatively regulate the receptor.

Thus, EGFR agonists also stimulate pathways that negatively regulate EGFR coupling to malignant phenotypes and the balance What is egfr in breast cancer these positive and negative regulation of EGFR coupling to malignant phenotypes may be altered in tumor cells. Several factors contribute to EGFR signaling specificity.

One is the presence of other ErbB family receptors. For example, ErbB2 can stabilize EGFR in a conformation that is competent for dimerization and tyrosine phosphorylation even in the absence of ligand binding, thereby contributing to ligand-independent EGFR signaling and increased ligand affinity for the EGFR [ 163334 ].

This results in phosphorylation of the heterodimerization partner ErbB2 or ErbB4 and may result in phosphorylation of a different set of EGFR tyrosine residues [ 1633 ].

These biological differences appear to be due to differences in the sites of agonist-induced EGFR tyrosine phosphorylation. The mechanism by which different ligands cause phosphorylation of distinct sets of EGFR tyrosine residues is unclear. Thus, ligand-specific differences in the juxtapositioning of the receptor monomers within the receptor dimer may lead to differences in receptor tyrosine residue availability to the receptor kinase domain for phosphorylation [ 17 ].

The roles that EGFR and its ligands play in breast cancer have been a subject of intensive study and controversy. Some retrospective immunohistochemical studies have indicated that EGFR overexpression in primary tumors is an indicator of poor prognosis [ 44 — 47 ], whereas other similar studies have failed to establish such a link [ 1048 ].

However, more extensive studies have failed to link ligand expression to prognosis [ 4952 ]. This apparent dichotomy may be explained by the fact that immunohistochemical analyses of ligand expression in tumor samples primarily detects the immature, transmembrane form of the ligand, whereas signaling might be driven largely by the mature soluble form of the ligand.

The development of platforms capable of simultaneously evaluating gene expression from a large portion of the genome has led to the identification of gene expression profiles that classify breast cancers. Basal-type breast cancers express markers frequently found in cells that are in contact with the basement membrane.

Such markers include keratin 5 and 17 basal keratinsP-cadherin, and troponin What is egfr in breast cancer 53 — 56 ]. Basal-type breast cancers are associated with large size, high tumor grade, poor survival, and increased frequency of distant metastases [ 56 ]. Given the relative aggressiveness of these tumors and the absence of targeted therapeutics for treating these tumors, the identification of targets for treating these tumors is a priority.

A low level of EGFR expression in basal tumors correlates with a reduced incidence of metastases [ 62 ]. Signaling pathways downstream of several different tyrosine kinases induce phosphorylation of AIB1, suggesting that EGFR signaling may cause Tam resistance via this mechanism [ 67 — 69 ]. A number of different tyrosine kinases may catalyze ER tyrosine phosphorylation, including ErbB2 [ 6869 ]. However, acquired resistance frequently arises, limiting the utility of this approach [ 68 ].

However, this hypothesis has yet to be tested in breast cancer patient samples. Solid tumors typically consist of a heterogeneous mix of cellular phenotypes that include poorly differentiated cells that undergo rapid cell division, differentiated cells that are incapable of cell division, and quiescent cells that possess the capacity for self-renewal and can give rise to the other types of tumor cells.

This self-renewal and pluripotency have led this category of cells to be called cancer stem cells or stem-like cancer cells [ 7273 ]. Breast cancer cells that have been What is egfr in breast cancer from pleural effusions exhibit a high level of CD44 expression and a low level of CD24 expression [ 74 ].

While these cells display a homogenous phenotype, they are extraordinarily efficient at forming phenotypically heterogeneous tumors in immunocompromised mice. Moreover, these cells readily form colonies in suspension cultures and exhibit very aggressive behaviors in metastasis and invasion assays [ 74 ].

ALDH1 has also emerged as a marker of tumor cells that exhibit stem-like characteristics [ 7576 ]. There is no direct evidence indicating that EGFR and its ligands are involved in the establishment or maintenance of breast tumor stem cells. Ligand-induced EGFR signaling is required for stem-like breast tumor cells including those derived from DCIS tumors to form colonies in semi-solid medium [ 77 ].

Overexpression of ErbB2 in mammary epithelial cells and breast cancer cell lines increases the fraction of cells that display stem-like properties [ 78 ]. Nonetheless, additional direct experimentation is necessary to evaluate this hypothesis. The most common metastasis Xnxx sex videos download of breast cancer is the bone [ 80 ].

Destruction of bone matrix is responsible for the fractures and bone pain associated with advanced breast cancer [ 81 ]. Bone metastases were largely refractory to the traditional systemic approaches radiation therapy and chemotherapy used to treat advanced breast cancer [ 808184 ].

Recently, the integration of the fields of basic bone cell biology and cancer biology has produced insights that have generated new and partially effective therapeutic approaches to this devastating form of metastasis.

Agents such as bisphosphonates reduce bone destruction and tumor growth by targeting the bone microenvironment rather than the tumor [ 84 ].

Recently, EGFR signaling has come into focus as a potential microenvironment target that could be exploited to reduce the morbidity associated with this form of metastasis. Metastasis to any organ features invasion of cancer cells through normal tissue into the blood stream initiationextravasation and infiltration of a distant tissue progressionand growth of a destructive colony within the new context virulence [ 85 ].

The genes that mediate these events are likely to be dispensable for primary tumor initiation and growth and may or may not be part of gene expression profiles exhibited by the primary tumor [ 85 ]. We have analyzed breast cancer transcriptome datasets from the NCBI Gene Expression Omnibus to compare the patterns of ErbB receptor and ligand in primary tumors that ultimately produced bone metastasis to the patterns found in tumors that failed to metastasize or produced metastases to other sites [ 59 — 61 ].

We have also compared ErbB receptor expression in a small set of bone metastasis samples with ErbB receptor expression in breast cancer samples removed from the lung, brain and liver [ 83 ].

However, we found little additional evidence for differential expression of ErbB family receptors. These findings suggest that EGFR signaling may be dysregulated in bone metastases through post-transcriptional events.

As indicated below, several emerging lines of evidence involving ligand-activating proteases support a role for the EGFR signaling in bone metastasis. Frequently, bone metastasis arise in breast cancer patients years after the identification and treatment of the primary tumor [ 87 ].

This implies that breast cancer cells remain dormant or indolent within the body. Individual or small groups of tumor cells found in the bone marrow of patients who lack discernable bone metastases are termed What is egfr in breast cancer tumor cells DTCs [ 87 ]. The presence of DTCs in the bone marrow is predictive of metastatic disease both in the bone and at other sites [ 87 — 89 ].

MDA-MB cells possess a basal phenotype [ 94 ] and various bone-seeking sublines have been What is egfr in breast cancer to dissect the molecular and cellular regulators of osteolytic growth of this cell line [ 9596 ].

This model holds that breast cancer cells direct the resident cells of bone to uncouple the physiological linkage between bone matrix destruction and new bone formation [ 96 ]. The MDA-MB cells produce cytokines and growth factors that engage in paracrine signaling with osteoclasts, cells that dissolve bone matrix, and osteoblasts, which are responsible for bone formation [ 9697 ].

In addition, osteoblasts produce colony-stimulating factor CSF-1which recruits monocytes from bone marrow progenitors that ultimately can be differentiated into osteoclasts in the presence of high levels of RANKL [ 96 ] [ 98What is egfr in breast cancer ]. The osteoclast-mediated destruction of bone releases growth factors embedded in the bone matrix.

There is growing evidence suggesting that EGFR signaling in osteoblasts directly contributes to osteolysis or bone resorption. EGFR is expressed by cultured osteoblasts, but not osteoclasts or monocytes []. Studies of bone biology suggest additional roles for EGFR ligands in the pathogenesis of osteolytic lesions. Exogenous EGFR ligands stimulate the proliferation of osteoblasts, inhibit their differentiation, and decrease their mineralization What is egfr in breast cancer ].

Moreover, 4-week-old transgenic mice lacking AREG expression exhibit less trabecular bone in the tibia than do wild-type littermates [ ]. Thus, EGFR signaling may mediate the What is egfr in breast cancer of PTH on the recruitment and expansion of cells committed to the osteoblast lineage, whereas excessive ligand signaling could prevent these cells from undergoing terminal differentiation and forming mineralized bone [ ].

The uncoupling of bone formation from the accelerated bone resorption would be a key feature of disease states like breast cancer-induced osteolysis. In the MDA-MB model, PTH receptor signaling is one of the key events in regulating the vicious cycle of breast cancer osteolysis and colonization [ ].

The pattern of PTHrP expression by breast cancers at various stages of progression resembles that displayed by metastasis virulence factors [ 85 ]. PTHrP expression is lower in primary breast What is egfr in breast cancer that ultimately metastasize to bone than in other primary breast tumors; however, PTHrP expression is very high among metastatic tumor cells within the bone microenvironment [ — ]. Analysis of MDA-MB subclones identified 11 genes whose overexpression is specific to clones that readily colonize the bone and form aggressive osteolytic lesions [ 95 ].

Moreover, combinations of 3 of these genes are sufficient to induce osteolytic growth by parental MDA-MB cells. Thus, these 11 genes appear to influence distinct events in the process of bone metastasis. These 11 genes also include the proteases MMP1 and ADAMTS-1 a disintegrin and metalloproteinase with thrombospondin motifswhose roles in bone metastasis were not readily apparent [ 95 ].

These findings suggest that EGFR ligands or the proteases that regulate their availability can serve as breast cancer metastasis virulence factors and that metastasis could be blocked by EGFR antagonists that have no apparent direct effect on the breast tumor cells themselves. Presumably, differences in the ability of breast tumor cells to colonize bone is regulated by proteases cleave AREG and enable What is egfr in breast cancer to stimulate EGFR signaling.

To summarize, the complex post-transcriptional regulation of EGFR ligand processing and receptor interactions provides mechanisms through which EGFR coupling to bone What is egfr in breast cancer may be enhanced. Thus, numerous gene products that contribute to EGFR signaling in breast tumor cells or osteoblasts may function as bone metastasis virulence factors.

Thus, deregulated signaling through the AREG-EGFR pathway may be a general mechanism by which multiple types of breast cancer form osteolytic bone metastases. Small-molecule What is egfr in breast cancer tyrosine kinase inhibitors and antagonistic anti-EGFR antibodies have exhibited little effect on primary tumor What is egfr in breast cancer or patient outcome in breast cancer monotherapy clinical trials.


© 2019
Magic porn » On the internet sex videos for real sex fans  arhicve