Breast Cancer and the Notch Signaling Pathway
Breast cancer is one of the most common genetic disorders. About one in three women are diagnosed with breast cancer in the United States (DeSantis 2013). Treatments such as chemotherapy are effective, but most of them do not work on cancer stem cells and metastatic tumors. Cancer stem cells are a type of cancer cells that can self-replicate indefinitely (Kai 2009). Researchers believe that they can break off from primary tumors and grow secondary tumors elsewhere in the body, which are more commonly known as metastatic tumors. Metastasis and recurrence cause the majority of breast-cancer related deaths (O’Shaughnessy 2005). In women who are diagnosed with breast cancer in its early stages, nearly 30% will have their cancers progress into Stage 4 breast cancer, or metastatic breast cancer (O’Shaughnessy 2005). It is imperative that treatments that are effective on metastatic tumors are found because metastatic tumors are responsible for many cancer patient deaths. Gene expressions of cancer stem cells are being studied in order to know why they do not respond to most chemotherapy. In addition, researchers are working to produce new treatments that can target cancer stem cells.
Figure 1- Notch Signaling Pathway. Source: Al-Hussaini 2011
One way to target cancer stem cells is by inhibiting the Notch signaling pathway, shown in Figure 1. In normal cells, the pathway is paramount in regulating cell proliferation, differentiation, homeostasis and apoptosis, or programmed cell death. Cancer cells have Notch signaling pathways that are deregulated. In breast cancer, Notch signaling helps stem cells grow tumors. Cells that are grown in the presence of a protein found in Notch signaling have ten times the ability to self-replicate than cells that grow in the absence of the protein (Al-Hussaini 2011). Notch signaling has receptors that have different purposes. The Notch1 receptor is involved in cell proliferation and resistance to chemotherapy (Yuan 2015b). Notch1 was found to be expressed seven times more in breast cancer cells than in normal cells (Yuan 2015a). Inhibiting Notch1 with a Notch1 antibody caused decreased rates in tumor growth and recurrence (Yuan 2015a). In addition, Notch signaling is largely expressed in disseminated cancer cells that broke away from primary tumors, showing that the pathway has connections to metastasis. If these disseminated cancer cells are identified and treated before they grow metastatic tumors, then metastatic cancer can be prevented. Inhibiting Notch signaling can be an effective treatment for controlling CSCs.
Gamma-secretase inhibitors (GSIs) can inhibit Notch signaling. GSIs inhibit enzymes involved in glycosylation and also cleave receptors. They have been shown to reduce tumor growth in several types of cancer and induce apoptosis in triple-negative breast cancer, which makes up 20% of all breast cancers (Al-Hussaini 2011). Clinical trials are being held to find an effective drug that can reduce Notch signaling by using GSIs.
There are other ways to target cancer stem cells and metastatic tumors. One way is by using mice to observe the effects of different chemotherapy drugs on tumors injected into mice. Lena Werb, a professor at the University of California, San Francisco (UCSF), is leading a lab that is studying tumors that were injected into mice. They found that metastatic tumors that were just created had different gene expressions than primary tumors (Weiler 2015). This is an important finding because this explains why metastatic tumors respond differently to chemotherapy than primary tumors do.
Cancer research has been growing rapidly in the past few decades. Treatments such as chemotherapy are much more advanced than they were in the 20th century. However, it is too early to get complacent about cancer research achievements. There are many effective treatments for primary tumors, but much is still unknown about cancer stem cells and metastatic tumors. In the next few decades of cancer research, there should be an increasing number of researchers working to uncover their mysteries so that more cancer-related deaths can be prevented.
Works Cited
Al-Hussaini H, Subramanyam D, Reedijik M, Sridhar SS. Notch Signaling Pathway as a Therapeutic Target in Breast Cancer. 2011 Molecular Cancer Therapy 10; 9-15.
DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. 2013 CA: A Cancer Journal for Clinicians 64; 52-62.
Kai K, Yoshimi A, Kamiya T, Saya H. Breast cancer stem cells. 2009 Breast Cancer 17; 80-85.
O’Shaughnessy J. Extending Survival with Chemotherapy in Metastatic Breast Cancer. 2005 The Oncologist 10; 20-29.
Weiler N. Metastatic Breast Cancer Cells Turn On Stem Cell Genes. 2015 UCSF.
Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S, Wu G, Wu K. Notch signaling: An emerging therapeutic target for cancer treatment. 2015b Cancer Letters 369; 20-27.
Yuan X, Zhang M, Wu H, Xu H, Han N, Chu Q, Yu S, Chen Y, Wu K. Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis. 2015a PLoS ONE 10.
