Interaction of developmental transcription factor HOXC11 with steroid receptor coactivator SRC-1 mediates resistance to endocrine therapy in breast cancer [corrected].
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.
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin D2, Ireland.
Marie
M
McIlroy
Damian
D
McCartan
Sarah
S
Early
Peadar
P
O Gaora
Stephen
S
Pennington
Arnold D K
AD
Hill
Leonie S
LS
Young
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000502:physiology; D050437:Genes, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009414:Nerve Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011485:Protein Binding / Q000502:physiology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; C484731:HOXC11 protein, human; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D014157:Transcription Factors; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1