TY - JOUR
T1 - Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer
AU - Cortez, Valerie
AU - Mann, Monica
AU - Tekmal, Seshidhar
AU - Suzuki, Takayoshi
AU - Miyata, Naoki
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
AU - Vadlamudi, Ratna K.
N1 - Funding Information:
The authors thank the Pathology Core Facility, University of Texas Health Science Center, San Antonio for performing IHC analysis, Dr Rajeshwar Rao Tekmal for nude mice studies, Dr Dimple Chakravarty for siRNA preparation/ transfection and Dr Sujit Nair for help with MTT assays. This study was supported by grants NIH-CA095681, NIH-1F31CA165814, NIH-CA165814-01 and U54 CA151668, the RGK Foundation, and Komen grant KG090447 1Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX 78229, USA. 2Department of Cell and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA. 3Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 403-8334, Japan. 4PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan. 5Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8673, Japan. 6Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 78030, USA. 7Center for RNA Interference and Non-coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX 78030, USA. 8Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 78030, USA. 9Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX 78229, USA.
PY - 2012/7/19
Y1 - 2012/7/19
N2 - Introduction: The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models.Methods: Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells.Results: Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment.Conclusion: Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.
AB - Introduction: The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models.Methods: Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells.Results: Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment.Conclusion: Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.
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U2 - 10.1186/bcr3229
DO - 10.1186/bcr3229
M3 - Article
C2 - 22812534
AN - SCOPUS:84864913725
VL - 14
JO - Breast Cancer Research
JF - Breast Cancer Research
SN - 1465-5411
IS - 4
M1 - R108
ER -