Functional Implications of Altered Subcellular Localization of PELP1 in Breast Cancer Cells

Abstract

It is increasingly accepted that steroidal receptor coregulators may also function in the cytoplasmic compartment. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel coregulator that plays a role in both the genomic and extranuclear actions of estrogen receptors (ER) in hormonally responsive tissues. In this study using breast tumor arrays, we found that PELP1 was localized only in the cytoplasm in 58% of the PELP1-positive breast tumors. To help explain the significance of the cytoplasmic localization of PELP1 in human breast tumors, we created a mutant protein that was expressed only in the cytoplasm (PELP1-cyto) and then generated a model system wherein MCF-7 breast cancer cells were engineered to specifically express this mutant. We found that PELP1-cyto cells were hypersensitive to estrogen but resistant to tamoxifen. PELP1-cyto cells, but not parental MCF-7 cells, formed xenograft tumors in nude mice. In addition, PELP1-cyto cells exhibited increased association of PELP1 with Src, enhanced mitogen-activated protein kinase (MAPK) activation, and constitutive activation of AKT. The altered localization of PELP1 was sufficient to trigger the interaction of PELP1 with the p85 subunit of phosphatidylinositol-3-kinase (PI3K), leading to PI3K activation. In addition, PELP1 interacted with epidermal growth factor receptors and participated in growth factor-mediated ER transactivation functions. Our results suggest that the altered localization of PELP1 modulates sensitivity to antiestrogens, potentiates tumorigenicity, presumably via the stimulation of extranuclear estrogen responses, such as the activation of MAPK and AKT, and also enhance cross-regulation of ER transactivation activity by growth factors. (Cancer Res 2005; 65(17): 7724-32)

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Effector molecules such as SHC-transforming protein 1, Akt, and MAPK are activated by adaptor protein Src and PI3K [62,63]. The crosstalk between E2 and other growth factor signals suggests that adaptor proteins are essential for extranuclear actions of ERα.…”

“…PELP1 contains ten LXXLL motifs that participate in the interaction with nuclear receptors and three proline-rich motifs that could participate in the interaction with proteins containing SH3 domains. PELP1 can act as an extranuclear adaptor protein between ERα and Src, thereby allowing E2-dependent activation of Src and the downstream ERK/MAPK signaling cascade [62]. This pathway confers tamoxifen resistance for breast cancer cells through the activation of both the PI3K/Akt and Src/MAPK pathways [62].…”

“…PELP1 can act as an extranuclear adaptor protein between ERα and Src, thereby allowing E2-dependent activation of Src and the downstream ERK/MAPK signaling cascade [62]. 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].…”

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

“…Estrogen independence in the presence of ER might arise via other mechanisms including the ligandindependent ER activation, expression of ER variants, and increased expression of co-activators (Gururaj et al, 2006). In addition, alteration of the complex interactions between ER and membrane-associated or cytoplasmic effectors might be involved in breast tumor progression as well as resistance to hormonal therapy (Vadlamudi et al, 2005).…”

Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway

“…PELP1 recruits to the ER target gene promoter, interacts with histones and histone-modifying enzymes, and is suggested to play a role in chromatin remodeling activity of the ligandbound ER (21). The ability of PELP1 to interact and couple cytosolic kinases c-Src and phosphatidylinositol-3-kinase to the ER highlights a novel role for PELP1 in nongenomic ER signaling (19,22,23). Recent evidence suggests that PELP1 is a potential proto-oncogene; its expression is deregulated during cancer progression (24).…”