Modulation of in Situ Estrogen Synthesis by Proline-, Glutamic Acid-, and Leucine-Rich Protein-1: Potential Estrogen Receptor Autocrine Signaling Loop in Breast Cancer Cells

Rajhans, Rajib; Nair, Hareesh B.; Nair, Sujit S.; Cortez, Valerie; Kijima, Ikuko; Kirma, Nameer B.; Zhou, Dujin; Holden, Alan E.C.; Brann, Darrell W.; Chen, Shiuan; Tekmal, Rajeshwar Rao; Vadlamudi, Ratna K.

doi:10.1210/me.2007-0350

Cited by 33 publications

(43 citation statements)

References 56 publications

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“…PELP1 also promotes local estrogen synthesis via Src kinase pathway facilitating growth of tumors in an autocrine manner [31]. Therefore, we hypothesized that PELP1 driven tumors can be therapeutically targeted using dasatinib and performed a proof of principle experiment using a post-menopausal xenograft model.…”

Section: Resultsmentioning

confidence: 99%

Significance of ER–Src axis in hormonal therapy resistance

Vallabhaneni

Nair

Cortez

et al. 2010

Breast Cancer Res Treat

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The estrogen receptor (ER) is implicated in the progression of breast cancer. Despite positive effects of hormonal therapy, initial or acquired resistance to endocrine therapies frequently occurs. Recent studies suggested ERα-coregulator PELP1 and growth factor receptor ErbB2/HER2 play an essential role in hormonal therapy responsiveness. Src axis couples ERα with HER2 and PELP1, thus representing a new pathway for targeted therapy resistance. To establish the significance of ER–Src axis in PELP1 and HER2 mediated therapy resistance, we have generated model cells that stably express Src-shRNA under conditions of PELP1, HER2 deregulation. Depletion of Src using shRNA substantially reduced E2 mediated activation of Src and MAPK activation in resistant model cells. Pharmacological inhibition of Src using dasatinib, an orally available inhibitor substantially inhibited the growth of therapy resistant MCF7–PELP1, MCF7–HER2, and MCF7–Tam model cells in proliferation assays. In post-menopausal xenograft based studies, treatment with dasatinib significantly inhibited the growth of therapy resistant cells. IHC analysis revealed that the tumors were ERα positive, and dasatinib treated tumors exhibited alterations in Src and MAPK signaling pathways. Combinatorial therapy of tamoxifen with dasatinib showed better therapeutic effect compared to single agent therapy on the growth of therapy resistant PELP1 driven tumors. The results from our study showed that ER–Src axis play an important role in promoting hormonal resistance by protooncogenes such as HER2, PELP1, and blocking this axis prevents the development of hormonal independence in vivo. Since PELP1, HER2, and Src kinase are commonly deregulated in breast cancers, combination therapies using both endocrine agents and dasatinib may have better therapeutic effect by delaying the development of hormonal resistance.

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Section: Resultsmentioning

confidence: 99%

Significance of ER–Src axis in hormonal therapy resistance

Vallabhaneni

Nair

Cortez

et al. 2010

Breast Cancer Res Treat

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“…The levels of PDZK1 decrease in tissues from women older than 55 years of age. It is tempting to speculate that this result may be linked to the decreasing levels of plasma estrogen (19,20). This potential connection becomes even more important in light of the report that intratumoral estrogen levels could reach levels as high as 20 times that detected in the plasma of affected individuals (21).…”

Section: Discussionmentioning

confidence: 98%

PDZK1 Is a Novel Factor in Breast Cancer That Is Indirectly Regulated by Estrogen through IGF-1R and Promotes Estrogen-Mediated Growth

Kim

Elmageed

et al. 2013

Mol Med

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Although a relationship between PDZK1 expression and estrogen receptor (ER)-α stimulation has been suggested, the nature of such a connection and the function of PDZK1 in breast cancer remain unknown. Human tissue microarrays (cancer tissue: 262 cores; normal tissue: 87 cores) and breast cancer cell lines were used to conduct the study. We show that PDZK1 protein expression is tightly correlated with human breast malignancy, is negatively correlated with age and had no significant correlation with ER-α expression levels. PDZK1 exhibited an exclusive epithelial expression with mostly cytosolic subcellular localization. Additionally, 17β-estradiol induced PDZK1 expression above its basal level more than 24 h after treatment in MCF-7 cells. PDZK1 expression was indirectly regulated by ER-α stimulation, requiring insulinlike growth factor 1 receptor (IGF-1R) expression and function. The molecular link between PDZK1 and IGF-1R was supported by a significant correlation between protein and mRNA levels (r = 0.591, p < 0.001, and r = 0.537, p < 0.001, respectively) of the two factors in two different cohorts of human breast cancer tissues. Interestingly, PDZK1 knockdown in MCF-7 cells blocked ER-dependent growth and reduced c-Myc expression, whereas ectopic expression of PDZK1 enhanced cell proliferation in the presence or absence of 17β-estradiol potentially through an increase in c-Myc expression, suggesting that PDZK1 has oncogenic activity. PDKZ1 also appeared to interact with the Src/ER-α/epidermal growth factor receptor (EGFR) complex, but not with IGF-1R and enhanced EGFR-stimulated MEK/ERK1/2 signaling. Collectively, our results clarify the relationship between ER-α and PDZK1, propose a direct relationship between PDZK1 and IGF-1R, and identify a novel oncogenic activity for PDZK1 in breast cancer.

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“…We failed to see any significant differences in the tumor latency in multiparous animals compared to nulliparous animals. Since our earlier studies showed that PELP1 deregulation induces local E2 synthesis via aromatase regulation (26) and such findings may explain to some extent the lack of exacerbate phenotype in PELP1 Tg multiparous animals, however, future studies are needed. Our ongoing studies will address the role of local estrogen in PELP1 mediated tumorgenesis and also test the effect of PELP1 overexpression on various stages of development of mammary gland.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Modulation of in Situ Estrogen Synthesis by Proline-, Glutamic Acid-, and Leucine-Rich Protein-1: Potential Estrogen Receptor Autocrine Signaling Loop in Breast Cancer Cells

Cited by 33 publications

References 56 publications

Significance of ER–Src axis in hormonal therapy resistance

Significance of ER–Src axis in hormonal therapy resistance

PDZK1 Is a Novel Factor in Breast Cancer That Is Indirectly Regulated by Estrogen through IGF-1R and Promotes Estrogen-Mediated Growth

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

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