Document Type

Paper

Publication Date

5-2017

Advisor(s)

Donald Dosch, PhD; Illinois Mathematics and Science Academy

Keywords

signaling transduction pathway, EMT, WNT, Integrin, HER 2/3, RTK, IGF-1, PI3K/AKT, TGF-β, TNF-α, Notch, Hypoxia, Hedgehog, PTCH, JAK, STAT3, RANK, TIMP-1, EGF, KISS1R, IL-6, OPN, Breast Cancer Metastasis, MAPK, Epithelial Mesenchymal Transition, SNAI1, Snail, SNAI2, Slug, ZEB1, ZEB2, Twist, E-cadherin

Description

Epithelial-Mesenchymal Transition (EMT) is a biological process utilized by epithelial cells to transform into motile mesenchymal cells, initiating metastasis in cancer. EMT is also utilized during development and wound healing [10]. This process allows for cancerous cells to detach themselves from their primary tumor and invade normal tissue in preferred organ sites, forming secondary tumors called metastases. Metastasis is very important in the progression of cancer in patients as it the process responsible for the mortality of patients through the collection of metastases that effect vital organs like the brain, lung, or immune system. The most common metastases for malignant breast tumors are the brain, lungs, lymph nodes, liver, and bone [1]. As metastasis increases the mortality rate of patients, it is vital to understand then how this process is initiated by EMT. EMT occurs due to epithelial cells losing their cell-cell adhesion and polarity. This is due to downstream targets of signal transduction pathways causing an integral step of EMT, the loss of epithelial cadherin (E-cadherin) expression. These downstream targets are zinc finger protein SNAI1 (Snail), zinc finger protein SNAI2 (Slug), zinc finger e-box binding homeobox 1 (ZEB1, TCF8), zinc finger e-box binding homeobox 2 (ZEB2, SIP1), and Twist-related protein 1 (Twist), that are known as EMT-associated transcription factors.

The second requirement for tumors to metastasize is the process of angiogenesis or lymphangiogenesis, which is the formation of new blood vessels or lymphatic vessels, respectively. Both processes allow for the primary tumor to connect to the blood stream or lymphatic system, allowing for mesenchymal cells to run through to invade healthy tissues. Both of these processes are initiated by the hypoxic conditions that the malignant tumor stimulates via its own metabolism and proliferation [148].

Despite the general understanding of how metastasis occurs, there are several signal transduction pathways involved in this process that are complicated. This paper aims to discuss an up-to-date understanding of these signal transduction pathways, their cross-talks, and role in metastasis, specifically in breast cancer metastasis. Figure 1 provides a visual of all of these signal transduction pathways that are discussed in this paper.

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