Coassociation of Estrogen Receptor and p160 Proteins Predicts Resistance to Endocrine Treatment; SRC-1 is an Independent Predictor of Breast Cancer Recurrence

Abstract

Purpose:This study investigates the role of the p160 coactivators AIB1and SRC-1independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments. Experimental Design: The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients. Results: Coassociation of the p160s and estrogen receptor a was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrinesensitive MCF-7 cells. In primary cultures, there was an increase in association of the coactivators with estrogen receptor a following estrogen treatment but dissociation was evident with tamoxifen. Immunohistochemical staining of the tissue microarray revealed that SRC-1 was a strong predictor of reduced disease-free survival (DFS), both in patients receiving adjuvant tamoxifen treatment and untreated patients (P < 0.0001 and P = 0.0111, respectively). SRC-1 was assigned a hazard ratio of 2.12 using a Cox proportional hazards model. Endocrine-treated patients who coexpressed AIB1with human epidermal growth factor receptor 2 had a significantly shorter DFS compared with all other patients (P = 0.03). Quantitative coassociation analysis in the patient tissue microarray revealed significantly stronger colocalization of AIB1and SRC-1with estrogen receptor a in patients who have relapsed in comparison with those patients who did not recur (P = 0.026 and P = 0.00001, respectively). Conclusions: SRC-1is a strong independent predictor of reduced DFS, whereas the interactions of the p160 proteins with estrogen receptor a can predict the response of patients to endocrine treatment.Adjuvant endocrine therapy offers substantial benefit in terms of reduction in risk of tumor recurrence in women with estrogen receptor -positive tumors. However, although most patients initially respond to tamoxifen, in 30% to 40% of cases these tumors recur within 5 years. This precipitates cessation of the regime and the initiation of second-line therapy. However, despite new targeted treatments for breast cancer, the vast majority of patients still depend on endocrine manipulation for management of their breast cancer.The magnitude of estrogen receptor gene regulation is influenced not only by the ligand but also by the presence of specific coregulatory proteins, present at rate-limiting levels, which modulate transcription. Over the past 10 years a number of nuclear receptor -interacting proteins have been isolated using various screening strategies. These include the p160 family coactivator proteins -steroid receptor coactivator-1 (SRC-1/NCoA-1), SRC-2 (TIF2/GRIP1), and SRC-3 (AIB1/ pCIP/RAC3/ACTR). The coactivator proteins drive nuclear receptor transcriptional activity by doing the significant reactions required for control of enhancer-d...

AIB1:ERα Transcriptional Activity Is Selectively Enhanced in Aromatase Inhibitor–Resistant Breast Cancer Cells

“…Data on the patients for both TMAs included tumor size, grade, lymph node status, HER2 status, and ER status. TMAs were constructed as previously described (2). Excluded from the analysis were patients who did not have breast surgery, those who had neoadjuvant therapy, or those whose tissue specimens were irretrievable.…”

“…This increase in growth factor signaling can result in ligandindependent activation of the steroid receptor, estrogen receptor (ER)a, and inappropriate recruitment of coactivator proteins, including AIB1 (2). AIB1 (SRC-3, TRAM-1, RAC3, NCoA3, ACTR, and p/CIP) is a member of the p160 nuclear receptor coactivator family and was identified as a gene frequently amplified in breast cancer (3).…”

“…In tamoxifen-treated patients, expression of AIB1 in conjunction with an activated HER2 cascade has been associated with treatment resistance and early disease recurrence (2). A direct role for AIB1, in ER-mediated transcriptional regulation of HER2, as well as in growth factor receptor signaling has recently been described (7,8).…”

Histone Modification and Breast Cancer

“…NCOA1 is overexpressed in 19% to 29% of breast cancers and plays important roles in cell proliferation, lymph node metastasis, disease recurrence and poor disease-free survival (DFS) (Fleming et al, 2004). Therefore, elevated www.intechopen.com NCOA1 has been regarded as an independent predictor of breast cancer recurrence following therapy (Redmond et al, 2009). Although the evidence were not very sufficient, NCOA2 overexpression might also promote proliferation and invasion of breast cancer cells (Kishimoto et al, 2005).…”

Steroid Receptor Coactivators and Their Expression, Regulation and Functional Role in Endocrine Responsive and Resistant Breast Cancer

“…Conversely, dissociation of SRC-3/AIB1 from ER restores tamoxifen's antagonistic effect in resistant breast cancer cells and inhibits further breast cancer cell growth (Planas-Silva et al, 2001;List et al, 2001). Clinically, studies have shown an association between SRC-1 and reduced disease-free survival in breast cancer patients with locally advanced disease treated with endocrine therapy (Al-azawi et al, 2008;Redmond et al, 2009). During neoadjuvant treatment with aromatase inhibitors, we found higher levels of SRC-1 mRNA levels during treatment, especially in tumors that responded to treatment (Flågeng et al, 2009).…”