The Unique Role of ER-α36 in Maintaining a Close Relationship between ER-α66 and HER2 in Breast Cancer
Jian Huang, Christopher R Chitambar, Behnaz Behmaram, Yee Chung Cheng, Zainab Basir, Alonzo Walker. Medical College of Wisconsin, Milwaukee, WI
Background: Many lines of evidence have demonstrated that crosstalk between wild-type estrogen receptor alpha (ER-α66) and human epidermal growth factor receptor 2 (HER2) plays a critical role in intrinsic and acquired resistance to both endocrine and HER2-directed neoadjuvant therapies. However, this paradigm has been challenged by clinical evidence that ER-α66 is co-expressed with HER2 in only 10% of ER-α66-positive breast cancer patients. Therefore, an intrinsic relationship between ER-α66 and HER2 needs to be identified. ER-α36, a novel splice variant of ER-α66, is expressed in both ER-α66-positive and ER-α66-negative breast tumors. Whether ER-α36 plays an unique role in maintaining a close relationship between ER-α66 and HER2 has not been explored.
Design: The expression of ER-α36, ER-α66 and HER2 was examined using immunohistochemistry (IHC) in two cohorts of 471 formalin-fixed, paraffin-embedded tissue microarray slides of breast tumors. We evaluated the correlations among ER-α36, ER-α66 and HER2, and confirmed their relationships in breast cancer cell lines. Statistical significance was measured using Fisher's exact test.
Results: The results showed that 1) ER-α66 is inversely associated with HER2 (P< 0.05); there is no relationship between ER-α66 and HER2 in ER-α36-negative tumors(P=1); Strikingly, there is a strong positive correlation between ER-α66 and HER2 in ER-α36-positive tumors (P<0.001). Knocking down ER-α36 expression by siRNA abrogated the interaction between ER-α66 and HER2 in both MCF7/HER2 and BT474 breast cancer cell lines. 2) ER-α36 is positively associated with ER-α66 (P<0.001); ER-α36 is more strongly associated with ER-α66 in HER2-negative tumors (P<0.0001); there is no association between ER-α36 and ER-α66 in HER2-positive tumors (P=0.78). 3) ER-α36 is also strongly positively associated with HER2(P<0.001); ER-α36 is more strongly associated with HER2 in ER-α66-negative tumors (P<0.0001); there is no association between ER-α36 and HER2 in ER-α66-positive tumors (P=0.14).
Conclusions: We demonstrated that there are strong dynamic relationships among ER-α36, ER-α66 and HER2 in breast cancer. ER-α36 plays a key role in maintaining such relationships. ER-α66 and HER2 are competitively associated with ER-α36. These results further suggest that ER-α36 may be a novel therapeutic target for overcoming resistance to both endocrine and HER2-directed neoadjuvant therapies.
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 22, Wednesday Afternoon