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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

Estrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway

Chiara Gorrini¹, Bevan P Gang, Christian Bassi

¹The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.

Proceedings of the National Academy of Sciences of the United States of America

|February 26, 2014

Abstract:

Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissue-specific nature of BRCA1's tumor suppression is obscure. We previously showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-deficient cells. Reactivation of NRF2 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells. Here we show that estrogen (E2) increases the expression of NRF2-dependent antioxidant genes in various E2-responsive cell types. Like NRF2 accumulation triggered by oxidative stress, E2-induced NRF2 accumulation depends on phosphatidylinositol 3-kinase-AKT activation. Pretreatment of mammary epithelial cells (MECs) with the phosphatidylinositol 3-kinase inhibitor BKM120 abolishes the capacity of E2 to increase NRF2 protein and transcriptional activity. In vivo the survival defect of BRCA1-deficient MECs is rescued by the rise in E2 levels associated with pregnancy. Furthermore, exogenous E2 administration stimulates the growth of BRCA1-deficient mammary tumors in the fat pads of male mice. Our work elucidates the basis of the tissue specificity of BRCA1-related tumor predisposition, and explains why oophorectomy significantly reduces breast cancer risk and recurrence in women carrying BRCA1 mutations.

Insights

BRCA1 mutations increase cancer risk. Estrogen (E2) reactivates the NRF2 antioxidant pathway in BRCA1-deficient cells, explaining tissue-specific tumor suppression and the benefits of oophorectomy.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Mutations in BRCA1 tumor suppressor gene increase breast and ovarian cancer risk.
The tissue-specific mechanism of BRCA1 tumor suppression is not well understood.
BRCA1-deficient cells exhibit defects in the NRF2-regulated antioxidant pathway.

Purpose of the Study:

To elucidate the mechanism of tissue-specific tumor suppression by BRCA1.
To investigate the role of estrogen (E2) in the NRF2 antioxidant pathway in BRCA1-deficient cells.
To explain the reduced breast cancer risk associated with oophorectomy in BRCA1 mutation carriers.

Main Methods:

Investigated E2-induced NRF2 activation in E2-responsive cell types.
Utilized phosphatidylinositol 3-kinase (PI3K) inhibitor BKM120 to block E2-induced NRF2 accumulation.
Assessed the effect of pregnancy-associated E2 levels on BRCA1-deficient mammary epithelial cells (MECs) in vivo.
Administered exogenous E2 to BRCA1-deficient mammary tumors in male mice.

Main Results:

Estrogen (E2) upregulates NRF2-dependent antioxidant genes in E2-responsive cells.
E2-induced NRF2 accumulation is dependent on phosphatidylinositol 3-kinase-AKT signaling.
PI3K inhibition prevents E2-mediated NRF2 activation in MECs.
Pregnancy-associated E2 levels rescue the survival defect in BRCA1-deficient MECs in vivo.
Exogenous E2 administration promotes BRCA1-deficient mammary tumor growth in male mice.

Conclusions:

Estrogen-mediated NRF2 pathway activation explains the tissue specificity of BRCA1 tumor suppression.
This mechanism clarifies why oophorectomy reduces breast cancer risk and recurrence in BRCA1 mutation carriers.

Read full analysis

Keywords:

PTEN breast cancer hormones reactive oxygen species

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