GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

Abrhale, T.; Brodie, Angela; Sabnis, Gauri; Macedo, Luciana F.; Tian, Changsheng; Yue, Binbin; Serrero, Ginette

doi:10.1186/1471-2407-11-231

Cited by 41 publications

(37 citation statements)

References 40 publications

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“…Moreover, PGRN treatment in MCF-7 cells inhibited the tamoxifen-induced down-regulation of bcl-2 [94]. PGRN may in addition interfere with aromatase therapy since PGRN inhibited the efficacy of the aromatase inhibitor letrozole in a human breast cancer cell line [95]. PGRN expression level was significantly increased in letrozole resistant tumor cells compared with letrozole sensitive cancer cells [95].…”

Section: Pgrn Cell Survival and Drug Resistancementioning

confidence: 84%

“…PGRN may in addition interfere with aromatase therapy since PGRN inhibited the efficacy of the aromatase inhibitor letrozole in a human breast cancer cell line [95]. PGRN expression level was significantly increased in letrozole resistant tumor cells compared with letrozole sensitive cancer cells [95]. Other hormone-based therapies may also be sensitive to PGRN production.…”

Section: Pgrn Cell Survival and Drug Resistancementioning

confidence: 99%

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The Glycoprotein Growth Factor Progranulin Promotes Carcinogenesis and has Potential Value in Anti-cancer Therapy

Zhang¹

2012

J Carcinogene Mutagene

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Progranulin (PGRN) is a secreted glycoprotein growth factor with tumorigenic roles in a variety of tumors including, among others, breast, ovarian, prostate, bladder, and liver cancer. In some patients, for example with breast, ovarian or liver cancers, high PGRN expression in tumors correlated with a worse outcome. Studies using cell lines and animal models provide evidence that PGRN promotes tumor cell proliferation, migration and survival, and induces drug resistance. Increasing or decreasing PGRN production enhances or inhibits respectively the growth of PGRN-sensitive tumors in vivo. PGRN activity is associated with p44/42 mitogen-activated protein kinase as well as phosphatidylinositol 3-kinases signaling pathways. In addition, PGRN may stimulate the formation of the tumor stroma. As an extracellular regulator of tumorgenesis, PGRN is a potential therapeutic target and biomarker of prognosis in the treatment of various cancers.

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Section: Pgrn Cell Survival and Drug Resistancementioning

confidence: 84%

Section: Pgrn Cell Survival and Drug Resistancementioning

confidence: 99%

The Glycoprotein Growth Factor Progranulin Promotes Carcinogenesis and has Potential Value in Anti-cancer Therapy

Zhang¹

2012

J Carcinogene Mutagene

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“…The combination treatment also disturbed the balance between proapoptotic (Bax) and antiapoptotic (Bcl-2) members through the inhibition of Bcl-2. Other research groups have reported that GEP overexpression led to the development of tamoxifen and letrozole resistance through the protection of Bcl-2 in breast cancers (36,37). The roles of Akt-PKB and MEK-ERK in apoptosis induced by cytotoxic drugs, and the interactions between the Akt-PKB pathways and Bcl-2 family members in the regulation of apoptosis have been described extensively (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Antibody against Granulin–Epithelin Precursor Sensitizes Hepatocellular Carcinoma to Chemotherapeutic Agents

Wong

Cheung

Yip

et al. 2014

Molecular Cancer Therapeutics

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Granulin-epithelin precursor (GEP) overexpression has been shown in many cancers with functional role on growth, and recently on regulating chemoresistance and cancer stem cell (CSC) properties. Here, we investigate the combined effect of GEP antibody and chemotherapeutic agent. Combination therapy was compared with monotherapy using hepatocellular carcinoma (HCC) cells in vitro and orthotopic liver tumor models in vivo. CD133 and related hepatic CSC marker expressions were investigated by flow cytometry. Antiproliferative and apoptotic effects and signaling mechanisms were examined by immunohistochemistry, flow cytometry, and Western blot analysis. Secretory GEP levels in the serum and culture supernatant samples were measured by ELISA. We demonstrated that HCC cells that survived under chemotherapeutic agents showed upregulation of hepatic CSC markers CD133/GEP/ABCB5, and enhanced colony and spheroid formation abilities. Importantly, GEP antibody sensitized HCC cells to the apoptosis induced by chemotherapy for both HCC cell lines and the chemoresistant subpopulations, and counteracted the chemotherapy-induced GEP/ABCB5 expressions and Akt/Bcl-2 signaling. In human HCC orthotopic xenograft models, GEP antibody treatment alone was consistently capable of inhibiting the tumor growth. Notably, combination of GEP antibody with high dose of cisplatin resulted in the eradication of all established intrahepatic tumor in three weeks. This preclinical study demonstrated that GEP antibody sensitized HCC cells to apoptosis induced by chemotherapeutic agents. Combination treatment with GEP antibody and chemotherapeutic agent has the potential to be an effective therapeutic regimen for GEP-expressing cancers. Mol Cancer Ther; 13(12); 3001-12. Ó2014 AACR.

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“…In addition, we have shown that GP88 confers resistance to the aromatase inhibitor letrozole in aromatase overexpressing cells MCF7-CA and AC1 cells while estrogen receptor expression remained unchanged [32]. Naturally letrozole resistant cells LTLT and AC1LTR cells overexpressed GP88 whereas inhibition of GP88 by SiRNA restored letrozole responsiveness [32]. Pathological studies with paraffin embedded breast cancer biopsies have shown positive GP88 tissue expression in 60% of ductal carcinoma in situ (DCIS) and 80% of invasive ductal carcinoma (IDC) whereas normal mammary epithelium and benign tumors were GP88 negative [33] In IDC, GP88 expression correlated with parameters of poor prognosis such as tumor grade, proliferation index and p53 expression.…”

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 96%

GP88 (Progranulin) Confers Fulvestrant (Faslodex, ICI 182,780) Resistance to Human Breast Cancer Cells

Tangkeangsirisin¹,

Serrero²

2014

ABCR

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The 88 kDa glycoprotein known as GP88, Progranulin or PC cell derived growth factor is an autocrine growth factor with a unique cysteine rich motif that is over expressed in breast cancer whereas it is negative in normal mammary epithelial cells. It has been shown to play a major role in estrogen independence, tamoxifen resistance and tumorigenesis of breast cancer cells. In the present study, we investigated the effect of GP88 overexpression on the response of the human breast cancer MCF-7 cells to the pure estrogen receptor antagonist fulvestrant (ICI 182,780). While fulvestrant effectively inhibited cell proliferation of empty vector transfected cells, it had no inhibitory effect on the proliferation of GP88 overexpressing breast cancer cells. Mouse xenograft experiments in athymic ovariectomized nude mice showed that GP88 over expressing cells were fulvestrant resistant in vivo in contrast to low GP88 expressing cells. We show that the ability of fulvestrant to induce apoptosis determined by measuring cleavage of poly (ADP-ribose) polymerase was inhibited by GP88. Anti-apoptotic activity of GP88 was associated with sustained expression of bcl-2 and bcl-xL after fulvestrant treatment. In contrast, fulvestrant was still able to inhibit the ability of estrogen to stimulate ERE-luciferase reporter gene activity as well as vEGF expression in GP88 over expressing MCF-7 cells similarly to control MCF-7 cells. Collectively, our data suggest that GP88 prevents apoptosis induced by faslodex and contributes to antiestrogen resistance in human breast cancer.

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GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

Cited by 41 publications

References 40 publications

The Glycoprotein Growth Factor Progranulin Promotes Carcinogenesis and has Potential Value in Anti-cancer Therapy

The Glycoprotein Growth Factor Progranulin Promotes Carcinogenesis and has Potential Value in Anti-cancer Therapy

Antibody against Granulin–Epithelin Precursor Sensitizes Hepatocellular Carcinoma to Chemotherapeutic Agents

GP88 (Progranulin) Confers Fulvestrant (Faslodex, ICI 182,780) Resistance to Human Breast Cancer Cells

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