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CYP1A1 regulates breast cancer proliferation and survival.

ABSTRACT: Cytochrome P450-1A1 (CYP1A1) is an extrahepatic phase I metabolizing enzyme whose expression is suppressed under physiologic conditions but can be induced by substrates via the aryl hydrocarbon receptor (AhR). Recent studies have shown that the majority of breast cancer tumors constitutively express CYP1A1. These findings led us to test the hypothesis that CYP1A1 promotes breast cancer progression by evaluating the effects of CYP1A1 knockdown on the proliferation and survival of the MCF7 and MDA-MB-231 lines. Independently of estrogen receptor status, CYP1A1 knockdown decreased colony formation, decreased cell proliferation, blocked the cell cycle at G0-G1 associated with reduction of cyclin D1, and increased apoptosis associated with reduction of survivin. CYP1A1 knockdown markedly increased phosphorylation of AMP-activated protein kinase (AMPK) and decreased phosphorylation of AKT, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and 70-kDa ribosomal protein S6 kinase (P70S6K). AMPK inhibition by compound C partially abrogated the proapoptotic effects of CYP1A1 knockdown, suggesting that effects of CYP1A1 knockdown are mediated in part through AMPK signaling. Consistent with CYP1A1 knockdown, pharmacologic reduction of CYP1A1 levels by the phytopolyphenol carnosol also correlated with impaired proliferation and induced AMPK phosphorylation. These results indicate that reduction of basal CYP1A1 expression is critical for inhibition of proliferation, which is not affected by ?-naphthoflavone-mediated inhibition of CYP1A1 activity nor modulated by AhR silencing. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival, at least in part, through suppression of AMPK signaling and that reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics.

SUBMITTER: Rodriguez M

PROVIDER: S-EPMC3720830 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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CYP1A1 regulates breast cancer proliferation and survival.

Rodriguez Mariangellys M Potter David A DA

Molecular cancer research : MCR 20130410 7

Cytochrome P450-1A1 (CYP1A1) is an extrahepatic phase I metabolizing enzyme whose expression is suppressed under physiologic conditions but can be induced by substrates via the aryl hydrocarbon receptor (AhR). Recent studies have shown that the majority of breast cancer tumors constitutively express CYP1A1. These findings led us to test the hypothesis that CYP1A1 promotes breast cancer progression by evaluating the effects of CYP1A1 knockdown on the proliferation and survival of the MCF7 and MDA ...[more]

PMID: 23576571

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Project description:BackgroundMusashi1 (Msi1) is a conserved RNA-binding protein that regulates the Notch and Wnt pathways, and serves as a stem cell marker in the breast and other tissues. It is unknown how Msi1 relates to other breast cancer markers, whether it denotes tumor initiating cells (TICs), and how it affects gene expression and tumor cell survival in breast cancer cells.ResultsMsi1 expression was analyzed in 20 breast cancer cell lines and in 140 primary breast tumors by western blotting and immunohistochemistry, respectively. Lentivirus RNA interference was used to reduce Msi1 expression in breast cancer cell lines MCF-7 and T47D grown as spheroid cultures and to assess stem cell gene expression and the growth of these cell lines as xenografts. In normal human breast tissue, Msi1 was expressed in 10.6% of myoepithelum and 1.2% of ductal epithelium in the terminal ductal lobular unit (TDLU), whereas, less than 0.05% of ductal epithelium and myoepithelium in large ducts outside the TDLU expressed Msi1. Msi1 was expressed in 55% of the breast cancer cell lines and correlated with ErbB2 expression in 50% of the cell lines. Msi1 was expressed in 68% of primary tumors and in 100% of lymph node metastases, and correlated with 5 year survival. Msi1 was enriched in CD133+ MCF-7 and T47D cells and in spheroid cultures of these cells, and Msi1 'knockdown' (KD) with a lentivirus-expressed shRNA decreased the number and size of spheroid colonies. Msi1 KD reduced Notch1, c-Myc, ErbB2 and pERK1/2 expression, and increased p21CIP1 expression, which is consistent with known Msi1 target mRNAs. Msi1 KD also reduced the expression of the somatic and embryonic stem cell markers, CD133, Bmi1, Sox2, Nanog and Oct4. Xenografts of MCF-7 and T47D Msi1 KD cells resulted in a marked reduction of tumor growth, reduced Msi1 and Notch1 expression and increased p21CIP1 expression.ConclusionMsi1 is a negative prognostic indicator of breast cancer patient survival, and is indicative of tumor cells with stem cell-like characteristics. Msi1 KD reduces tumor cell survival and tumor xenograft growth, suggesting that it may represent a novel target for drug discovery.

Project description:Radixin is an important member of the Ezrin-Radixin-Moesin protein family that is involved in cell invasion, metastasis and movement. microRNA (miR)-200b is a well-studied microRNA associated with the development of multiple tumors. Previous bioinformatics analysis has demonstrated that miR-200b has a complementary binding site in the 3'-untranslated region of radixin mRNA. The present study aimed to investigate the role of miR-200b in regulating radixin expression, cell proliferation and invasion in breast cancer. Breast cancer tissues at different Tumor-Node-Metastasis (TNM) stages were collected; breast tissues from patients with hyperplasia were used as a control. miR-200b and radixin mRNA expression levels were tested by reverse transcription-quantitative PCR. Radixin protein expression was detected by western blotting. The highly metastatic MDA-MB-231 cells were divided into four groups and transfected with a miR-negative control (NC), miR-200b mimic, small interfering (si)RNA-NC or siRNA targeting radixin. Cell invasion was evaluated by Transwell assay and cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine staining. Compared with the control group, radixin mRNA expression was significantly higher in breast cancer tissues and increased with TNM stage. miR-200b expression levels exhibited the opposite trend. Radixin mRNA expression in breast cancer cells was notably higher, whereas miR-200b expression was lower compared with that in normal breast epithelial MCF-10A cells. The expression of radixin was higher, whereas miR-200b was lower in MDA-MB-231 cells compared with that in MCF-7 cells. miR-200b mimic or siRNA-radixin transfection downregulated the expression of radixin in MDA-MB-231 cells and attenuated the invasive and proliferative abilities of these cells. miR-200b-knockdown and radixin overexpression were associated with enhanced cell invasion in breast cancer. In conclusion, miR-200b regulates breast cancer cell proliferation and invasion by targeting radixin expression.

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CYP1A1 regulates breast cancer proliferation and survival.

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CYP1A1 regulates breast cancer proliferation and survival.

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