Centchroman suppresses breast cancer metastasis by reversing epithelial–mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling

Khan, Sajid; Shukla, Samriddhi; Sinha, Sonam; Lakra, Amar Deep; Bora, Himangsu K.; Meeran, Syed Musthapa

doi:10.1016/j.biocel.2014.10.028

Cited by 54 publications

(64 citation statements)

References 43 publications

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“…Previously, we have demonstrated the in vitro anti‐proliferative effect of CC against multiple human breast cancer cells . We reported that CC inhibits the cellular proliferation at lower concentrations and induces cellular apoptosis at comparatively higher concentrations in human breast cancer cells.…”

Section: Resultsmentioning

confidence: 96%

“…CC is a synthetic triphenylethylene compound which has been shown to possess anti‐cancer potential against human breast cancer cells . Recently, we have also reported the CC‐mediated suppression of breast cancer metastasis by reversal of EMT accompanied with the downregulation of HER2/ERK1/2/MMP‐9 signaling . Since, cancer is a manifestation of both genetic and epigenetic changes, we further sought to investigate the effect of CC on the epigenetic alterations in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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Centchroman altered the expressions of tumor‐related genes through active chromatin modifications in mammary cancer

Khan

Shukla

Sinha

et al. 2015

Molecular Carcinogenesis

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Centchroman (CC), a female oral contraceptive, has been shown to possess breast anti-cancer activities. Recently, we have shown CC-mediated antimetastatic effect through reversal of epithelial-to-mesenchymal transition (EMT) in breast cancer. The loss of tumor suppressor genes (TSGs) has been shown to promote EMT in breast cancer. Therefore, in the present study, we investigated the effect of CC-treatment on the expression of tumor-related genes including both tumor suppressor- and tumor promoter genes in breast cancer. CC treatment resulted in G /G phase cell cycle arrest in human breast cancer MDA-MB-231, SK-BR-3, and ZR-75-1 cells with the concomitant induction of TSGs such as p21 , p16 , and p27 . In addition, CC treatment also resulted in the downregulation of tumor promoter gene, human telomerase reverse transcriptase (hTERT). The induction of TSGs and downregulation of hTERT was found to be correlated with decreased expression levels of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Further, mechanistic studies revealed CC-induced global DNA demethylation and alterations in the enrichment of chromatin modification markers at the promoters of p21 and hTERT. These in vitro results were corroborated with in vivo findings in 4T1-syngeneic mouse model, where CC-treatment resulted in tumor growth reduction accompanied with the induction of TSGs and alterations in the expression levels of HDACs, DNMT1, and histone modification markers. Overall, our findings suggest that CC-treatment induces the expression of TSGs and downregulates hTERT through histone modifications and DNA methylation changes. Therefore, CC could be further developed into a promising drug candidate against breast cancer. © 2015 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Centchroman altered the expressions of tumor‐related genes through active chromatin modifications in mammary cancer

Khan

Shukla

Sinha

et al. 2015

Molecular Carcinogenesis

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“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”

Section: Other Associated Micromoleculesmentioning

confidence: 99%

“…Further, Khan et al (2015) recently revealed CC could further be developed as an effective drug candidate for the fact that CC-treatment at higher doses specifically induces cellular apoptosis and inhibits cellular proliferation; whereas at lower doses, it inhibits cellular migration and invasion. against metastatic breast cancer.…”

Section: Other Treatmentsmentioning

confidence: 99%

“…against metastatic breast cancer. (Khan et al, 2015), and one possible mechanism may be reversing epithelial-mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling; and Afatinib, an irreversible ErbB family blocker, covalently binds to EGFR, HER2, and ErbB4, and thus irreversibly block signaling from all homo-and heterodimersformed by the ErbB family members, differs from lapatinib and trastuzumab by its broader scope of ErbB receptor inhibition and by its covalent mode of binding resulting in potent and long-lasting activity. (Rimawi et al, 2014) Finally, Taspase1, a highly conserved threonine protease, cleave (mixed-lineage leukemia) MLL which forms complexes with E2F transcription factors to regulate Cyclins E, A, and B expression, required for HER2/neuinduced tumor genesis (Dong et al, 2014).…”

Section: Other Treatmentsmentioning

confidence: 99%

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Recent Progress in HER2 Associated Breast Cancer

Wang¹,

Lei²,

Mei³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Nonhormonal selective estrogen receptor modulator 1‐(2‐[4‐{(3R,4S)‐7‐Methoxy‐2, 2‐dimethyl‐3‐phenyl‐chroman‐4yl}phenoxy]ethyl)pyrrolidine hydrochloride (ormeloxifene hydrochloride) for the treatment of breast cancer

Pillai

Regidi

Varghese

et al. 2018

Drug Development Research

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Breast cancer is the most common type of diagnosed cancers in women, difficult to treat, and has received international attention because of its aggressive nature and inherent drug resistance mechanisms. Development of a better selective estrogen receptor modulator with good therapeutic profile and less toxicity is very crucial in this scenario. This study was undertaken to evaluate and compare the in vitro and in vivo antitumor activities of ormeloxifene with other clinically used breast cancer drugs. Cytotoxic activity of ormeloxifene was compared with standard drugs, 4‐hydroxytamoxifene and Adriamycin. Ormeloxifene (50 μM) concentration showed cytotoxicity of 75% and 82% in MDAMB‐231 and 24% and 80% in MCF‐7 cells, respectively, after 72 and 144 hr of incubation as displayed by cell viability assay. The same concentration of ormeloxifene was shown to exert 74% caspase‐7 activation in MCF‐7 cells after 24 hr of incubation by fluorescence resonance energy transfer assay. Cell cycle analysis proved that there was an increase in sub‐G1 peak to 64.4% and 33.9% in MDAMB‐231 and MCF‐7 cells, respectively, after treatment using ormeloxifene (50 μM) for 48 hr. The nonobese diabetic‐severe combined immunodeficiency mice bearing tumor xenografts of triple negative MDAMB‐231 cells treated with ormeloxifene (3 mg/kg bw) showed significant regression in relative tumor volume compared to control. From the results obtained and as evidenced from prior literature, ormeloxifene in addition to contraceptive use, can be repositioned for the development of an efficacious anticancer drug. These data present the preclinical part of a well concerted effort to place ormeloxifene into further clinical trials.

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Centchroman suppresses breast cancer metastasis by reversing epithelial–mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling

Cited by 54 publications

References 43 publications

Centchroman altered the expressions of tumor‐related genes through active chromatin modifications in mammary cancer

Centchroman altered the expressions of tumor‐related genes through active chromatin modifications in mammary cancer

Recent Progress in HER2 Associated Breast Cancer

Nonhormonal selective estrogen receptor modulator 1‐(2‐[4‐{(3R,4S)‐7‐Methoxy‐2, 2‐dimethyl‐3‐phenyl‐chroman‐4yl}phenoxy]ethyl)pyrrolidine hydrochloride (ormeloxifene hydrochloride) for the treatment of breast cancer

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