Extranuclear Coactivator Signaling Confers Insensitivity to Tamoxifen

Abstract

Purpose: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-α-positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance. Experimental Design: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness. Results: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase and AKT as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration, indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers proliferating cell nuclear antigen and activated mitogen-activated protein kinase than in untreated PELP1-cyto cell-derived mice. We also found that nude mice with MCF-7/PELP1-cyto cell-derived tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplasmic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen compared with patients whose tumors had low levels of cytoplasmic PELP1. Conclusions: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active nongenomic signaling.The steroid hormone 17-β estradiol is known to exert its cellular effects in tissues by binding to its major target, the estrogen receptor-α. Estrogen receptor, a ligand-dependent transcription factor, has been implicated in the progression of breast cancer, as evidenced by the fact that almost 70% of breast tumors are estrogen receptor-positive at the time of early diagnosis (1, 2). Currently, tamoxifen represent one of many available standard treatments for estrogen receptor-positive breast cancer patients (3), although most patients who respond to tamoxifen eventually acquire tamoxifen resistan...

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…This pathway confers tamoxifen resistance for breast cancer cells through the activation of both the PI3K/Akt and Src/MAPK pathways [62]. PELP1-transgenic mice, which express cytoplasmic PELP1 in mammary gland tumors, display tamoxifen resistance, suggesting that these extranu-clear actions are responsible for the drug resistance [76]. PELP1 has also been implicated in aromatase regulation in breast cancer cells through a short extranuclear auto-crine loop between E2 and aromatase expression [77].…”

Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer

“…In breast cancer studies, PELP1 is restricted to the nucleus of normal MEC but is partially to largely cytoplasmic in a significant number of breast tumors in which its altered localization is associated with tamoxifen resistance (Vadlamudi et al 2005, Kumar et al 2009). Mechanistic studies conducted in cancer cell lines demonstrated that altered localization of PELP1 to the cytoplasm augments intracellular c-Src, MAPK, and AKT signaling (Fig.…”

The social network of PELP1 and its implications in breast and prostate cancers

“…Several studies have indicated that the deregulation of PELP1 contributes to therapy resistance and that the knockdown of PELP1 or blockage of PELP1-mediated extranuclear signaling sensitizes cells to therapy , Nagpal et al 2008, Kumar et al 2009. Interestingly, the subcellular localization of PELP1 is dysregulated in tumors with a cytosolic predominance in a subset of endometrial tumors, which exhibit resistance to tamoxifen anti-hormonal therapy.…”

“…Interestingly, the subcellular localization of PELP1 is dysregulated in tumors with a cytosolic predominance in a subset of endometrial tumors, which exhibit resistance to tamoxifen anti-hormonal therapy. Patients whose tumors have high levels of cytoplasmic PELP1 respond poorly to tamoxifen therapy compared with patients whose tumors have low levels of cytoplasmic PELP1 (Kumar et al 2009). These observations are in agreement with results from an experiment in which tamoxifen-susceptible MCF-7 cells engineered to express PELP1 in cytosol (by modification the nuclear localization sequence) were found to exhibit resistance to tamoxifen , Kumar et al 2009, Gonugunta VK, Sareddy GR, Krishnan SR, Cortez V, Roy SS, Tekmal RR & Vadlamudi RK, 2014.…”