Dataset Information

Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer.

ABSTRACT: Genetic variants in CYP19A1, the gene encoding aromatase, have been reported to be associated with circulating estrogen concentrations, a key risk factor for breast cancer. The mechanism underlying this association is still unclear; it has been suggested that some of these variants may alter the expression and/or activity of aromatase. Here we analyzed the expression of intra-tumoral CYP19A1 messenger RNA (mRNA) and the genotypes of rs10046, a well-characterized single nucleotide polymorphism in CYP19A1, in 138 breast cancer patients and 15 breast cancer cell lines. The genotype TT was detected in 36 patients and six cell lines, genotype CT in 55 patients and five cell lines, and genotype CC in 28 patients and four cell lines. We found no evidence for a significant association of CYP19A1 levels with rs10046 genotypes, although expression tended to be higher in tumors and cell lines with the homozygous risk genotype TT. We also found no evidence for a significant association of rs10046 genotypes with breast cancer prognosis. In contrast, high CYP19A1 expression was highly significantly associated with a poor overall, disease-free, and metastasis-free survival in estrogen receptor-positive but not negative breast cancer patients. Moreover, CYP19A1 mRNA was significantly elevated in postmenopausal patients and in patients older than 50 years, and a trend towards a positive correlation with ER status and ESR1 mRNA expression was observed. These findings highlight the key role of aromatase in estrogen receptor-positive breast cancer biology.

SUBMITTER: Friesenhengst A

PROVIDER: S-EPMC5862917 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer.

Friesenhengst Andrea A Pribitzer-Winner Tamara T Miedl Heidi H Pröstling Katharina K Schreiber Martin M

Hormones & cancer 20180123 2

Genetic variants in CYP19A1, the gene encoding aromatase, have been reported to be associated with circulating estrogen concentrations, a key risk factor for breast cancer. The mechanism underlying this association is still unclear; it has been suggested that some of these variants may alter the expression and/or activity of aromatase. Here we analyzed the expression of intra-tumoral CYP19A1 messenger RNA (mRNA) and the genotypes of rs10046, a well-characterized single nucleotide polymorphism in ...[more]

PMID: 29363090

Similar Datasets

Project description:LESSONS LEARNED:Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)-resistant breast cancer are limited. Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor-positive and AI-resistant disease in this phase II, single-arm study. The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage. BACKGROUND:Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR-positive triple-negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)-positive and AR-positive advanced breast cancer. METHODS:A Simon's two-stage, phase II, single-arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ?4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression-free survival (PFS), and tolerability. RESULTS:A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow-up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated. CONCLUSION:Bicalutamide in combination with another AI did not show synergistic activity in patients with ER-positive breast cancer and AI resistance. Results suggest that no more large-sample clinical trials should be conducted in this population for overcoming endocrine resistance.

Project description:In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor ? (ER?), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen-ER?-induced cell proliferation. In ER?-containing cancer cells, the estrogen, 17?-estradiol (E2) activates the UPR through a phospholipase C ? (PLC?)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ER? blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLC?, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ER? activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6?, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ER?-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ER?(+) breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ER? proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.

Dataset Information

Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer.

Publications

Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets