Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1

Abstract

Background: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. Aim: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. Methods: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. Results: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p,0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). Conclusion: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.

Inverse relationship between ER-β and SRC-1 predicts outcome in endocrine-resistant breast cancer

“…We and others have described altered recruitment of coactivator proteins to the ER in the presence of oestrogen and ER modulators (Bai and Giguere, 2000;Margeat et al, 2003;Fleming et al, 2004a). We have previously observed that SRC-1 protein expression was associated with resistance to endocrine therapy (Fleming et al, 2004a) and the growth factor receptor HER2 (Fleming et al, 2004b). Here, we describe a significant inverse association between SRC-1 and DFS.…”

“…Recent studies have reported positive associations between AIB1 protein expression, high tumour grade and coexpression with the coactivators p300/ CBP (Hudelist et al, 2003). We have previously described a positive relationship between SRC-1 expression and resistance to endocrine therapy (Fleming et al, 2004a) and have observed a significant association between both SRC-1 and AIB1 and the proto-oncogene HER2 (Fleming et al, 2004b).…”

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

“…Noteworthy, ovariectomized female SRC-1 -/-mice have decreased uterine growth and reduced mammary gland ductal side branching and alveolar formation in response to estrogen compared with wild-type mice, indicating a role of SRC-1 in estrogen-regulated breast development (Xu et al, 1998;Xu & Li, 2003). We found higher SRC-1 mRNA levels by real-time RT-PCR in human breast cancer samples compared to normal breast tissue (Haugan Moi et al, 2010), and the same has been observed at the protein level (Hudelist et al, 2003;Fleming et al, 2004b;Myers et al, 2004). SRC-1 protein expression in breast cancer has been reported to associate positively with human epidermal growth factor receptor 2/neu (HER-2/neu) and negatively with ER (Fleming et al, 2004b).…”

Interactions between the estrogen receptor, its cofactors and microRNAs in breast cancer

“…More recently, it is suggested that tumors with increased expression of the coactivator SRC-1 have a greater probability of developing tamoxifen resistance, if they also overexpress the epidermal growth factor receptor, HER2/ neu [51]. This is also seen in breast tumors expressing high levels of SRC-3 [33].…”