Coassociation of ERα and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence.

Abstract

#3032 The p160 coactivators AIB1 and SRC-1 are known to play a critical role in modulating transcription in breast cancer cells in conjunction with ligand-bound estrogen receptor. The interactions of the p160 proteins with this nuclear receptor are also important in the development of resistance to endocrine treatments. Using quantitative coassociation immunofluorescent microscopy, the colocalisation of the p160s and ERα was increased in the LY2 endocrine resistant cell line following treatment with the anti-estrogen tamoxifen in comparison to the endocrine sensitive MCF-7 cell line. In cell cultures derived from patient tumours at the time of primary surgery prior to treatment, there was an increase in association of the coactivators with ERα following treatment with estrogen but dissociation was evident in the presence of tamoxifen. Immunohistochemical staining of a tissue microarray, constructed from 560 breast cancer patients, revealed that SRC-1 was a strong predictor of reduced disease-free survival, both in patients receiving adjuvant tamoxifen treatment and untreated patients (p<0.0001 and p=0.0111 respectively). AIB1 was not a significant independent predictor of disease recurrence. SRC-1 was assigned a hazard ratio of 2.12 when survival analysis using a Cox proportional hazards model was applied. Quantitative coassociation analysis of the p160 coactivators with ERα in the patient TMA revealed significantly stronger colocalisation of SRC-1 and ERα in patients who are known to have relapsed than those patients who did not recur (p=0.00001). This data suggests SRC-1 is pivotal in tumour aggressiveness and is a powerful predictor of progression of disease in breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3032.

The role of oestrogen receptor α in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2

“…The magnitude of ER gene regulation is influenced not only by the ligand, but also by the presence of specific co-regulatory proteins, present at rate-limiting levels, which modulate transcription. Studies from our group in breast cancer suggest that while expression of the coactivator protein SRC-1 correlates with reduced time to disease recurrence, the presence of the corepressor NCoR predicts enhanced disease-free survival (Myers et al 2005, Al-azawi et al 2008, Redmond et al 2009). In the thyroid patient population, NCoR was found exclusively in the non-anaplastic tumours and normal thyroid tissue.…”

“…In the setting of breast cancer, these molecular switches have been shown to be prognostically significant , McIlroy et al 2006. Aberrant expression of p160 proteins has been associated with resistance to endocrine therapies and the development of tumour recurrence (Osborne et al 2003, Redmond et al 2009). Furthermore, unlike other oncogenes, recent studies provide evidence of a specific role for SRC-1 in the development of metastasis (Qin et al 2009, Wang et al 2009).…”

Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer

“…Molecular and clinical studies have confirmed SRC-1 as a significant biomarker of poor disease-free survival (2,3). In a large, well-defined breast cancer cohort, strong associations were observed between SRC-1 and HOXC11 and between each of these proteins and their putative target gene Figure 5.…”

“…In support of these observations, we found that treatment of resistant cells with 4-OHT increased nuclear localization and expression of HOXC11. Ex vivo associations between coactivators and transcription factors provide evidence of disease progression in breast cancer patients (2). Steroid-dependent functional interactions between SRC-1 and HOXC11 were detected in primary cell cultures derived from breast cancer patient tumors.…”