Role of 4E-BP1 and the Unfolded Protein Response in Triple Negative Breast Cancer Cell Survival
Publication Date
July 2019
Location
LSU Health Medical Education Building
Document Type
Abstract
Start Date
26-7-2019 9:00 AM
End Date
26-7-2019 12:00 PM
Description
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This disease is associated with high metastasis and poor prognosis and constitutes 15-20% of all breast cancers. As a heterogeneous subtype lacking normal hormone receptors, TNBC proves difficult to treat. Extensive research is now being conducted to identify biomarkers and novel therapeutic treatments for this invasive cancer. Previous research has demonstrated that the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress plays a crucial role in TNBC cell survival and metastasis. The UPR is responsible for reducing the protein translational load on the ER under cellular stresses such as nutrient deprivation, which is common in the tumor microenvironment. While the UPR enables cell survival for a period of time, prolonged ER stress prompts the UPR to activate apoptotic signaling. TNBC, however, manipulates the UPR to evade cell death and continue cell growth even under sustained ER stress. A key regulator of protein synthesis that is differentially expressed in TNBC is the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), which binds to eIF4E in order to prevent translation at the 5’ cap of an mRNA transcript. Although 4E-BP1 functions as a negative regulator of eIF4E and therefore as a tumor suppressor, cancers like TNBC utilize deregulation of 4E-BP1 to promote internal ribosome entry site (IRES) translation of specific oncogenic proteins. Furthermore, ATF4, a transcription factor involved in UPR signaling, has been shown to activate 4E-BP1 production. Recent findings suggest that 4E-BP1 may also regulate ATF4 expression in a positive feedback loop. We set out to determine the role of 4E-BP1 and the UPR in the IRES-dependent translation of oncogenic proteins in TNBC cells. In this study, we found that 4E-BP1 is overexpressed and more active under cellular stress, correlating to an increase in ATF4 expression. Knockdown of 4E-BP1 prompts a decrease in ATF4 expression, suggesting that 4E-BP1 is both regulated by and mediates expression of ATF4. Expression of c-MYC, a protein containing an IRES sequence, also strongly decreases when 4E-BP1 is silenced, which suggests that 4E-BP1 may regulate IRES translation activation. We aim to apply these findings to the development of potential therapeutic targets of this deadly cancer.
Recommended Citation
Bickerton, Caroline F., "Role of 4E-BP1 and the Unfolded Protein Response in Triple Negative Breast Cancer Cell
Survival" (2019). Summer Research Internship Program. 4.
https://digitalscholar.lsuhsc.edu/srip/2019/undergrad/4
Role of 4E-BP1 and the Unfolded Protein Response in Triple Negative Breast Cancer Cell Survival
LSU Health Medical Education Building
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This disease is associated with high metastasis and poor prognosis and constitutes 15-20% of all breast cancers. As a heterogeneous subtype lacking normal hormone receptors, TNBC proves difficult to treat. Extensive research is now being conducted to identify biomarkers and novel therapeutic treatments for this invasive cancer. Previous research has demonstrated that the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress plays a crucial role in TNBC cell survival and metastasis. The UPR is responsible for reducing the protein translational load on the ER under cellular stresses such as nutrient deprivation, which is common in the tumor microenvironment. While the UPR enables cell survival for a period of time, prolonged ER stress prompts the UPR to activate apoptotic signaling. TNBC, however, manipulates the UPR to evade cell death and continue cell growth even under sustained ER stress. A key regulator of protein synthesis that is differentially expressed in TNBC is the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), which binds to eIF4E in order to prevent translation at the 5’ cap of an mRNA transcript. Although 4E-BP1 functions as a negative regulator of eIF4E and therefore as a tumor suppressor, cancers like TNBC utilize deregulation of 4E-BP1 to promote internal ribosome entry site (IRES) translation of specific oncogenic proteins. Furthermore, ATF4, a transcription factor involved in UPR signaling, has been shown to activate 4E-BP1 production. Recent findings suggest that 4E-BP1 may also regulate ATF4 expression in a positive feedback loop. We set out to determine the role of 4E-BP1 and the UPR in the IRES-dependent translation of oncogenic proteins in TNBC cells. In this study, we found that 4E-BP1 is overexpressed and more active under cellular stress, correlating to an increase in ATF4 expression. Knockdown of 4E-BP1 prompts a decrease in ATF4 expression, suggesting that 4E-BP1 is both regulated by and mediates expression of ATF4. Expression of c-MYC, a protein containing an IRES sequence, also strongly decreases when 4E-BP1 is silenced, which suggests that 4E-BP1 may regulate IRES translation activation. We aim to apply these findings to the development of potential therapeutic targets of this deadly cancer.
Comments
Mentor: Dr. Francesca Peruzzi, Stanley S. Scott Cancer Center