PELP1 Overexpression in the Mouse Mammary Gland Results in the Development of Hyperplasia and Carcinoma

Abstract

Estrogen receptor coregulator over-expression promotes carcinogenesis and/or progression of endocrine related-cancers in which steroid hormones are powerful mitogenic agents. Recent studies in our laboratory, as well as others, demonstrated that the estrogen receptor coregulator PELP1 is a proto-oncogene. PELP1 interactions with histone demethylase KDM1 play a critical role in its oncogenic functions and PELP1 is a prognostic indicator of decreased survival in breast cancer patients. However, the in vivo significance of PELP1 deregulation during initiation and progression of breast cancer remains unknown. We generated an inducible, mammary gland–specific PELP1-expressing transgenic (Tg) mouse (MMTVrtTA-TetOPELP1). We found more proliferation, extensive side branching and precocious differentiation in PELP1-overexpressing mammary glands than in control glands. Aged MMTVrtTA-TetOPELP1 bitransgenic mice had hyperplasia and preneoplastic changes as early as 12 weeks, and ER-positive mammary tumors occurred at a latency of 14–16 months. Mechanistic studies revealed that PELP1 deregulation altered expression of a number of known ER target genes involved in cellular proliferation (such as cyclin D1, CDKs) and morphogenesis (EGFR, MMPs) and such changes facilitated altered mammary gland morphogenesis and tumor progression. Further, PELP1 was hyper-phosphorylated at its CDK phosphorylation site, suggesting an autocrine loop involving the CDK–cyclin D1–PELP1 axis in promoting mammary tumorigenesis. Treatment of PELP1 Tg mice with a KDM1 inhibitor significantly reduced PELP1 driven hyper branching, reversed alterations in cyclin D1 expression levels and reduced CDK-driven PELP1 phosphorylation. These results further support the hypothesis that PELP1 deregulation has the potential to promote breast tumorigenesis in vivo and represent a novel model for future investigation into molecular mechanisms of PELP1-mediated tumorigenesis.

Cytoplasmic Localization of Proline, Glutamic Acid, Leucine-rich Protein 1 (PELP1) Induces Breast Epithelial Cell Migration through Up-regulation of Inhibitor of κB Kinase ɛ and Inflammatory Cross-talk with Macrophages

“…Herein, we show that PELP1-cyto expression induces a multiacinar phenotype that is most similar to what has been observed with ErbB2 expression in MCF-10A cells (40). In a mouse model, mammary gland-specific PELP1 overexpression promotes hyperplasia and tumor formation of ER-positive carcinoma (12). A PELP1-cyto mammary gland specific mouse model has also been shown to induce hyperplasia and increase activation of Erk and Akt signaling (11).…”

“…Mutant PELP1 with an altered nuclear localization sequence results in a protein that is predominately cytoplasmic (PELP1-cyto) and leads to activation of cytoplasmic signaling in breast cancer cell line models (10). In mammary-specific transgenic mouse models, expression of wild-type PELP1 or PELP1-cyto induced mammary gland hyperplasia that was associated with increased Akt and Erk1/2 signaling (11,12). Cytoplasmic PELP1 signaling has primarily been studied in breast cancer cell line models and in vivo mouse models (10,11,13).…”

PELP1 signaling contributes to medulloblastoma progression by regulating the NF‐κB pathway

“…Several reports have shown that PELP1 downregulation significantly reduced the proliferation, survival, migration, and invasion of cancer cells in multiple cancer types . Recently, we demonstrated that PELP1 overexpression contributes to mammary gland carcinoma using a tissue‐specific transgenic mouse model . PELP1 plays a role in ER‐positive metastases via extranuclear ER‐Src‐PELP1‐ILK1 pathway and knockdown of PELP1 reduced the invasion and metastasis of TNBC cells .…”

PELP1: Structure, biological function and clinical significance

“…Overexpression of PELP1 in the mammary gland using transgenic mice model contributed to mammary gland carcinoma, further supporting its oncogenic potential in vivo (Cortez et al 2014). PELP1 oncogenic signaling is implicated in progression of several cancers including breast (Krishnan et al 2015; Zhang et al 2015), endometrial (Vadlamudi et al 2004) ovarian (Chakravarty 2008), salivary (Vadlamudi et al 2005a), prostate (Yang et al 2012), lung (Slowikowski et al 2015), pancreas (Kashiwaya et al 2010) and colon (Ning et al 2014).…”

“…EGF can promote PELP1 phosphorylation at CDK sites (Olsen et al 2006). Studies using inducible transgenic mice model revealed that PELP1 regulates expression of a number of known ESR1 target genes involved in cellular proliferation including cyclin D1 and CDKs, and that PELP1 was hyper-phosphorylated at its CDK phosphorylation site, suggesting an autocrine loop involving the CDK–cyclin D1–PELP1 axis in promoting mammary tumorigenesis (Cortez et al 2014). …”