Unknown

Dataset Information

0

Reversal of endocrine resistance in breast cancer: interrelationships among 14-3-3?, FOXM1, and a gene signature associated with mitosis.


ABSTRACT: Despite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. 14-3-3 ?/YWHAZ, a member of the 14-3-3 family of conserved proteins, is over-expressed in several types of cancer, and our previous work showed that high expression of 14-3-3? in ER-positive breast cancers was associated with a poor clinical outcome for women on tamoxifen. Therefore, we now probe the role of 14-3-3? in endocrine resistance, and we examine the functional dimensions and molecular basis that underlie 14-3-3? activities.From analyses of four independent breast cancer microarray datasets from nearly 400 women, we characterized a gene signature that correlated strongly with high expression of 14-3-3? in breast tumors and examined its association with breast cancer molecular subtypes and clinical-pathological features. We investigated the effects of altering 14-3-3? levels in ER-positive, endocrine sensitive and resistant breast cancer cells on the regulation of 14-3-3? signature genes, and on cellular signaling pathways and cell phenotypic properties.The gene signature associated with high 14-3-3? levels in breast tumors encompassed many with functions in mitosis and cytokinesis, including aurora kinase-B, polo-like kinase-1, CDC25B, and BIRC5/survivin. The gene signature correlated with early recurrence and risk of metastasis, and was found predominantly in luminal B breast cancers, the more aggressive ER-positive molecular subtype. The expression of the signature genes was significantly decreased or increased upon reduction or overexpression of 14-3-3? in ER-positive breast cancer cells, indicating their coregulation. 14-3-3? also played a critical role in the regulation of FOXM1, with 14-3-3? acting upstream of FOXM1 to regulate cell division-signature genes. Depletion of 14-3-3? markedly increased apoptosis, reduced proliferation and receptor tyrosine kinase (HER2 and EGFR) signaling, and, importantly, reversed endocrine resistance.This study reveals that 14-3-3? is a key predictive marker for risk of failure on endocrine therapy and serves a pivotal role impacting growth factor signaling, and promoting cell survival and resistance to endocrine therapies. Targeting 14-3-3? and its coregulated proteins, such as FOXM1, should prove valuable in restoring endocrine sensitivity and reducing risk of breast cancer recurrence.

SUBMITTER: Bergamaschi A 

PROVIDER: S-EPMC3218959 | BioStudies | 2011-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-01-01 | S-EPMC4303117 | BioStudies
2013-01-01 | S-EPMC3663086 | BioStudies
2011-01-01 | S-EPMC4337964 | BioStudies
2014-08-07 | E-GEOD-55204 | ArrayExpress
2020-01-01 | S-EPMC7605433 | BioStudies
1000-01-01 | S-EPMC2898598 | BioStudies
2018-01-01 | S-EPMC6077722 | BioStudies
2019-01-01 | S-EPMC6652714 | BioStudies
2008-01-01 | S-EPMC2500166 | BioStudies
2011-01-01 | S-EPMC3624623 | BioStudies