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ER Re-expression and Re-sensitization to Endocrine Therapies in ER-negative Breast Cancers

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Abstract

Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERα in breast cancers is an important prognostic indicator. About 30–40% of breast cancers lack detectable ERα protein. ERα− breast cancers are resistant to endocrine therapies and have a worse prognosis than ERα+ breast cancers. Since expression of ERα is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERα− phenotype and develop interventions to restore ERα expression in ERα− breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERα expression and in these cases; demethylation of the ERα promoter or treatment with HDAC inhibitors shows promise in restoring ERα expression in ERα− breast cancers. Two additional potential mechanisms underlying generation of the ERα− phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERα− breast cancer and can drive the proteasomal degradation of ERα. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERα− phenotype and that inhibition of MAPK activity can cause re-expression of the ERα and restore sensitivity to endocrine therapies. Given the challenges in treating ERα− breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERα are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERα− breast cancers.

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Abbreviations

ERα:

estrogen receptor alpha

ERE:

estrogen response element

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

MAPK:

mitogen-activated protein kinase

Her2:

hairy-related 2

erbB2:

v-erb-b2 erythroblastic leukemia viral oncogene homolog 2

TGF-α:

transforming growth factor alpha

E2:

estradiol

HDAC:

histone deacetylase

DNMT:

DNA methyltransferase

SAHA:

Suberoylanilide hydroxamic acid

AZA:

5-aza-2’-deoxycytide

TSA:

Trichostatin A

PAK1:

p21 protein (Cdc42/Rac)-activated kinase 1

AKT:

serine/threonine protein kinase Akt

PR:

progesterone receptor

Src:

v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog

E6-AP:

ubiquitin protein ligase E3A

HSP:

heat shock protein

Pl3K:

phosphoinositide 3-kinase

SHC:

SH2 Containing Protein

PKC:

Protein kinase C

ERK:

Extracellular Signal Regulated Kinases

JNK:

c-Jun N-terminal Kinase

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Authors and Affiliations

  1. University of Miami, Miller School of Medicine, Department of Medicine, Sylvester Comprehensive Cancer Center, Room 410 Papanicolau Building, 1550 N.W. 10th Avenue, Miami, FL, 33136, USA

    Joeli A. Brinkman & Dorraya El-Ashry

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  1. Joeli A. Brinkman
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  2. Dorraya El-Ashry
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Correspondence to Dorraya El-Ashry.

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Brinkman, J.A., El-Ashry, D. ER Re-expression and Re-sensitization to Endocrine Therapies in ER-negative Breast Cancers. J Mammary Gland Biol Neoplasia 14, 67–78 (2009). https://doi.org/10.1007/s10911-009-9113-0

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  • DOI: https://doi.org/10.1007/s10911-009-9113-0

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