Abstract P4-02-16: Investigating the role of NRIP1 as a novel marker and therapeutic target for breast cancer

Abstract

Abstract Background:. Tamoxifen and fulvestrant target estrogen receptor (ER), which is overexpressed in more than 80% of breast cancer (BC) cases, and have significantly improved the survival rate. However, in most metastatic cases, resistance is inevitable. Identifying gene targets for improving the efficiency of hormone therapy, delaying the progress of resistance development, and restoring the efficacy of hormone therapy has great significance. Epidemiological studies of human populations found that early age at menarche significantly associates with the risk of BC. Remarkably, a five-year delay in menarche has been shown to correspond to a 35% reduction of BC. This suggests that identifying genes that regulate female sexual maturation (FSM) might provide a novel approach for exploring the genetic and molecular mechanisms of BC, providing clues in the search for new therapeutic targets. We previously identified and verified that nuclear receptor interacting protein 1 (Nrip1, also named Rip140) is a regulator of female sexual maturation. NRIP1, a co-regulator of nuclear receptors, interacts with several known signaling pathways for BC, such as E2F and estrogen receptor (ER). Human genome-wide association studies suggested that polymorphisms of NRIP1 are significantly associated with the risk of BC. Furthermore, elevating NRIP1 can promote epithelial cells proliferation and increase the development rate and size of the mammary gland, while depleting NRIP1 expression has the opposite effect. Importantly, clinical studies suggested that breast cancer patients with higher level of NRIP1 have a relatively poorer prognosis. Experiments and results:. 1. To investigate the role of NRIP1 in BC, we first measured NRIP1 expression in cancers. We found that NRIP1 was overexpressed in the tissues of BC and the BC cell lines. Importantly, immunohistochemistry assay showed that that NRIP1 is elevated in BC cell lines and tissues from patients with BC. Interestingly, overexpressed NRIP1 accumulated in the cytoplasm of the stromal cells in the benign tumors; but, in the malignant tumors, there was more accumulation in the nuclei of epithelia. Further studies revealed that suppressing NRIP1 could increase apoptosis of cancer cells in vitro and suppress the initiation and growth of DMBA (7,12-Dimethylbenz(a)anthracene) induced breast tumors. 2. Our previous studies have shown that deletion of NRIP1, in a variety of cell types, could suppress the activity of NFκB, which promotes the development of hormone therapy resistance; therefore, indicating that the suppression of NRIP1 may also suppress hormone therapy resistance. To test this hypothesis, we induced tamoxifen resistance in MCF7, which is estrogen receptor positive. During the induction, we found that NRIP1 expression increased gradually with the development of tamoxifen resistance. Interestingly, along with the upregulation of NRIP1 expression, we found that NRIP1 was translocated from the cytosol into the nucleus. These results suggest that not only the level of NRIP1 expression, but also the location, are related to the development of tamoxifen resistant. Furthermore, we found that suppressing the expression of NRIP1 by siRNA in tamoxifen resistant MCF7 (MCF7-TR) could significantly reduce the percentage of cells in the S phase and increase apoptosis with or without tamoxifen treatment. Conclusion:. 1. Investigating the genetic regulation of FSM may provide clues for identifying novel BC related genes. 2. NRIP1 plays an important role in BC. 3. Inhibiting NRIP1 may suppress the initiation and growth of BC. 4. NRIP1 overexpression and nuclear translocation are involved in the development of hormone therapy resistance. 5. The deletion of NRIP1 can suppress the development tamoxifen resistance in vitro. Citation Format: Yun Zhu, Fawwad Zaidi, Krishna Rao, Rong Yuan. Investigating the role of NRIP1 as a novel marker and therapeutic target for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-16.