TEORIA ORGANIZACIONAL ACERCA DE LOS ENTORNOS DE

2. MARCO TEORICO

2.1. TEORIA ORGANIZACIONAL ACERCA DE LOS ENTORNOS DE

The Ras – MAPK signaling cascade plays important roles in the progression of breast cancer. This is not meant to be a comprehensive review, rather to provide background sufficient to understand data presented herein. There are four major mitogen-associated protein kinase (MAPK) signaling cascades in humans, all of which end with transcriptional activity performed by the association of the MAP kinase in the pathway with nuclear transcriptional factors. These four effector MAP kinases are Erk1/2, Erk5, Jnk, and p38188_{. Generally, Erk1/2 and Erk5 are responses to extracellular} growth factor stimulation, whereas Jnk and p38 are associated with cellular stress signals188–190. As the present work only involves Erk1/2, it is only necessary to discuss this MAPK effector and its upstream factors, focusing on the signaling cascade followed by the in vitro and in vivo influences of this signaling cascade on breast cancer progression. Finally, the clinical relevance of this pathway is described.

Figure 6. The Ras - MAPK and PI3K - Akt signaling pathways

A simplified representation of the Ras – MAPK and PI3K – Akt signaling networks, illustrating the crosstalk between the pathways using a receptor tyrosine kinase (RTK) common input. Phosphorylation of the intracellular domain of RTK (for example, EGFR) attracts the SH2 domain of Grb2, which subsequently attracts Sos-1 through its SH3 domain. Sos-1 acts as a guanine exchange factor (GEF) for Ras, converting it into the “on” state. Ras signals

downstream through Raf and PI3K as its major effectors. PI3K signals through Akt whereas Raf signals through Mek1/2, then Erk1/2, to activate transcriptional programs that lead to growth migration and survival. RTKs can also

directly signal through PI3K. Phosphorylated Akt can suppress Raf activity as one of the mechanisms of crosstalk between these two signaling networks. Inhibitors of PI3K (LY294002) and Mek1/2 (PD98059) signaling are

Since Erk1/2 signaling commonly begins with growth factors binding to the extracellular domain of receptor tyrosine kinases (RTKs), EGFR activation will be used to illustrate this signaling pathway (Figure 6). EGFR binds ligand, which induces receptor homo- or hetero- dimerization and phosphorylation of the cytoplasmic receptor tails158. Phosphorylation of the EGFR intracellular domain recruits proteins harboring SH2 and PTB binding domains, such as Grb2191,192. In turn, Grb2 associates through its SH3 domain with the guanine exchange factor (GEF) Sos-1193,194_{. Sos-1 catalyzes the exchange of GDP for GTP on several small signaling G-} proteins, such as Ras, which acts as an activation signal. Importantly, in order to associate with Sos-1, Ras must be tethered to either the plasma membrane or lipid rafts through prenyl groups195.

After activation, Ras recruits Raf to the membrane through the latter’s Ras binding domain (RBD), which removes Raf auto-inhibition and allows for partial activation of Raf kinase activity by its phosphorylation by other membrane kinases, such as CK2 and Shc196,197_{. Dimerization of} Raf induces its catalytic activity and results in the recruitment of Mek1/2 and its phosphorylation and activation197. Activated Mek1/2 subsequently phosphorylates and activates Erk1/2, which translocates to the nucleus and interacts with transcription factors such as Elk1 and Elf1 to induce transcription of target genes197,198. Importantly for breast cancer, nuclear Erk1/2 can interact with and activate the estrogen receptor198_{. Finally, feedback inhibition of this MAPK cascade acts as an} important regulatory mechanism whereby, for example, active Erk1/2 phosphorylates upstream proteins at inhibitory sites to reduce downstream activation of the pathway199.

Erk1/2 signaling in breast cancer can be described as either independent of or dependent on estrogen signaling. Estrogen independent Erk1/2 activity is traditionally due to upstream signals from growth factors, such as EGF, TGFα, and IGF-1, which transmit mitogenic and migratory signals down the MAPK cascade200. In contrast, estrogen dependent Erk1/2 activity can occur from

both immediate (signal-based) and late (genomic) effects. Estrogen can activate Erk1/2 within five minutes of stimulation in ER positive MCF-7 breast cancer cells, which is due in part to activation of c-Src201. Similarly, the estrogen receptor mediates transcription of growth factors such as TGFα and IGF-1, which can subsequently act in an autocrine or paracrine manner to enhance Erk1/2 activity202. Importantly, enhanced Erk1/2 activity is commonly found in breast cancers subjected to anti-estrogen therapies, suggesting this pathway serves as an adaptation mechanism. For example, breast cancer xenografts formed from long-term estrogen deprived cells were more sensitive to the mitogenic effects of estrogen than their wild type counterparts, which was due to increased MAPK activity in the former203. Moreover, breast cancer cells resistant to anti-estrogen therapies rely in part on Erk1/2 activation for cell growth204.

Hyper-activation of Erk1/2 is common in breast cancer pathologic specimens. For example, there is a 5-fold upregulation in both phosphorylation and protein expression of Erk1/2 in breast carcinoma as compared to benign pathologies, such as fibroadenoma205, and similar upregulation compared to matched control tissue206,207. Likewise, Erk1/2 activity is further increased in lymph node metastases as compared to primary breast tumors, suggesting it plays an important role in the metastatic cascade207. Moreover, highly activated MAPK signatures are associated with loss of estrogen receptor expression in clinical breast cancer specimens, decreased responsiveness to anti- estrogen therapy, and poor prognosis208–210.

In summary, the Ras – MAPK signaling pathway, focusing specifically on Erk1/2 as the downstream effector, is commonly dysregulated in breast cancer. Mitogenic and migratory signals from Erk1/2 originate from growth factor stimulation, through EGFR and other RTKs, and from estrogen stimulation, through the estrogen receptor and c-Src. Enhanced Erk1/2 activity in breast

cancer is a resistance mechanism to anti-estrogen therapy, is implicated in tumor metastasis, and bears poor clinical prognosis.

In document Validación de la versión en español del instrumento practice environment scale of the nursing work index (pes- nwi o“entorno laboral de la práctica de enfermería”) / Spanish version of the practice environment scale of the nursing work index (página 32-35)