Phosphorylation of the Mutant K303R Estrogen Receptor α at Serine 305 Impacts Aromatase Inhibitor Sensitivity

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Oncogene (Impact Factor: 8.46). 04/2010; 29(16):2404-14. DOI: 10.1038/onc.2009.520
Source: PubMed


We earlier identified a lysine to arginine transition at residue 303 (K303R) in estrogen receptor alpha (ERalpha) in invasive breast cancers, which confers resistance to the aromatase inhibitor (AI) anastrozole (Ana) when expressed in MCF-7 breast cancer cells. Here, we show that AI resistance arises through an enhanced cross talk of the insulin-like growth factor receptor-1 (IGF-1R)/insulin receptor substrate (IRS)-1/Akt pathway with ERalpha, and the serine (S) residue 305 adjacent to the K303R mutation has a key function in mediating this cross talk. The ERalpha S305 residue is an important site that modifies response to tamoxifen; thus, we questioned whether this site could also influence AI response. We generated stable transfectants-expressing wild-type, K303R ERalpha or a double K303R/S305A mutant receptor, and found that the AI-resistant phenotype associated with expression of the K303R mutation was dependent on activation of S305 within the receptor. Ana significantly reduced growth in K303R/S305A-expressing cells. Preventing S305 phosphorylation with a blocking peptide inhibited IGF-1R/IRS-1/Akt activation and also restored AI sensitivity. Our data suggest that the K303R mutation and the S305 ERalpha residue may be a novel determinant of AI response in breast cancer, and blockade of S305 phosphorylation represents a new therapeutic strategy for treating tumors resistant to hormone therapy.


Available from: Anna Tsimelzon, Mar 12, 2014
    • "Another mutation at nucleotide 908 of ERα (A908G) has been identified in premalignant breast hyperplasia's and invasive breast tumors from untreated patients [137, 138]. Molecular analysis of K303R ERα reveals that mutated arginine at the 303 position accelerates the phosphorylation of PKA [139] and AKT [140] . Enhanced growth factor receptor cross-talk with ER and alteration in ER structures leads to drug resistance in breast cancer [115]. "
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    • "Leptin effect on both HER2 and Hsp90 expression were also reproduced in ERa-negative and HER2-overexpressing SKBR3 breast cancer cells, suggesting that it may represent a general mechanism not related to cell specificity. Several mechanisms are responsible for the development of the endocrine resistance in breast cancer, and among these, increased expression and/or signaling of growth factor receptors have been extensively studied (Arpino et al., 2004; Barone et al., 2009; Schiff et al., 2003 ). Experimental and clinical studies have suggested that both de novo and acquired resistance to antiestrogen Tamoxifen in breast cancer can be associated with elevated levels of HER2 (Chung et al., 2002; Gutierrez et al., 2005; Meng et al., 2004; Shou et al., 2004 ). "
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