Abstract
Mechanisms of acquired resistance to endocrine therapy in breast cancer, a major clinical challenge, are poorly understood. We have used a mass spectrometry-based screen to identify proteins that are associated with the endocrine-resistant phenotype. In this study, we report the identification of a novel pathway of resistance to endocrine therapy involving interactions of the developmental transcription HOXC11 with the steroid receptor coactivator protein SRC-1, which is a strong predictor of reduced disease-free survival in breast cancer patients. HOXC11 and SRC-1 cooperate to regulate expression of the calcium-binding protein S100beta in resistant breast cancer cells. Nuclear HOXC11 and S100beta were found to strongly predict poor disease-free survival in breast cancer patients (n = 560; hazard ratios: 5.79 and 5.82, respectively; P < 0.0001). Elevated serum levels of S100beta detected in patients also predicted reduced disease-free survival (n = 80; hazard ratio: 5.3; P = 0.004). Our findings define a biomolecular interaction network that drives an adaptive response to endocrine therapy with negative consequences for survival in breast cancer.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents, Hormonal / therapeutic use*
-
Breast Neoplasms / diagnosis
-
Breast Neoplasms / drug therapy*
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism
-
Case-Control Studies
-
Disease-Free Survival
-
Drug Resistance, Neoplasm* / genetics
-
Female
-
Gene Expression Regulation, Neoplastic
-
Gene Regulatory Networks / physiology
-
Genes, Developmental / physiology
-
Homeodomain Proteins / genetics
-
Homeodomain Proteins / metabolism*
-
Humans
-
Nerve Growth Factors / blood
-
Nerve Growth Factors / genetics
-
Nerve Growth Factors / metabolism
-
Nuclear Receptor Coactivator 1 / genetics
-
Nuclear Receptor Coactivator 1 / metabolism*
-
Prognosis
-
Protein Binding / physiology
-
S100 Calcium Binding Protein beta Subunit
-
S100 Proteins / blood
-
S100 Proteins / genetics
-
S100 Proteins / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Tumor Cells, Cultured
Substances
-
Antineoplastic Agents, Hormonal
-
HOXC11 protein, human
-
Homeodomain Proteins
-
Nerve Growth Factors
-
S100 Calcium Binding Protein beta Subunit
-
S100 Proteins
-
Transcription Factors
-
NCOA1 protein, human
-
Nuclear Receptor Coactivator 1