Migliaccio, Ilenia (2010) Estrogen receptor co-regulators as prognostic and predictive markers of endocrine therapy in early breast cancer: the role of SMRT and p160 family. [Tesi di dottorato] (Unpublished)

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Background: The estrogen receptor (ER) signaling pathway is the dominant driver of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, endocrine treatment, such as the anti-estrogen tamoxifen, represents the most effective and widely used therapy for ER positive breast cancer patients. Unfortunately not all patients respond to endocrine treatment and a wide proportion of patients ultimately develop resistance and die. Selecting patients with an increased risk of recurrence and identifying those that might benefit from a particular therapy is of great value in order to personalize breast cancer therapies. A minority of breast cancers does not express ER and displays features of aggressiveness and poor prognosis. Prognostic markers are urgently needed for this subset of patients as well. The p160 family of ER co-activator is composed of three different members: SRC1, SRC2 and AIB1. SRC1 and AIB1 are frequently overexpressed in breast cancer and appear to be linked to hormone resistance, particularly in HER2 positive breast cancer. SMRT is an ER co-repressor that has been implicated in tamoxifen resistance. Data on p160 family members and SMRT expression in human breast cancer samples and its prognostic and predictive significance in endocrine treated patients are controversial or lacking altogether. Moreover, the role of these co-regulators in ER negative disease is poorly understood. Methods: SRC1, SRC2, AIB1 and SMRT expression was determined by immunohistochemistry on tissue microarrays derived from two fully documented cohorts of 1812 and 1424 patients. Results: HER2 and AIB1 dual-positive tumors were associated with markedly worse outcome compared to tumors overexpressing either HER2 or AIB1 alone, irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. Additionally, we found that co-expression of two or more SRCs were significantly associated with worse outcome in ER positive endocrine-treated patients. However, expression of any SRC alone was not a significant predictor of resistance to endocrine therapy. Low nuclear SMRT expression was associated with a significantly better outcome in untreated patients but not in tamoxifen-treated patients. Conclusions: The SRC family of ER co-activators and nuclear SMRT are markers of early relapse in both ER negative and ER positive breast cancer. Evaluation of multiple markers co-expression (i.e. AIB1/HER2, multiple SRCs) rather than single markers allows a better assessment of breast cancer prognosis.

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