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
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.
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[Show abstract] [Hide abstract] ABSTRACT: Abstract: Estrogens along with their receptors are required for the normal physiological development of women. However, in altered physiological conditions a high level of estrogens acts either as initiator or progressor of breast cancer. Approximately in 75% of estrogen dependent breast cancer cases estrogen receptors (ERs) are held responsible. Recent studies indicate that estrogens along with iron (Fe) concomitantly involved in the proliferation of ER+ breast cancer cells. While a number of antiestrogen/anti-ER drugs including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective estrogen receptor down regulators (SERDs) are used to eradicate breast cancer but their action on Fe dependent breast cancer complication is not yet explored. Moreover, many of the ER+ breast cancer patients receiving anti-estrogen drugs relapsed within a couple of years and become resistant to antiestrogen therapy. Mutation and loss of affinity to the target molecule (ERs), loss or overexpression of ERs, along with activation of growth promoting pathways alternative to estrogen-ER pathways are the major reasons of drug resistance. Combinational therapy may be best alternative to antiestrogen relapsed patients. Some of the widely studied drug combinations are roscovitine (ROSC) and tamoxifen, metformin and tamoxifen, tamoxifen and RAD001. While in all these drug combinations anti-ER compound tamoxifen may be one of the major content, anti-Fe compounds are yet to be used as drug combination. The present review article describes all the currently studied drugs/drug combinations in ER+ breast cancer cells and future drug possibilities including anti-Fe compounds.
- "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  and AKT  . Enhanced growth factor receptor cross-talk with ER and alteration in ER structures leads to drug resistance in breast cancer . "
[Show abstract] [Hide abstract] ABSTRACT: Obesity condition confers risks to breast cancer development and progression, and several reports indicate that the adipokine leptin, whose synthesis and plasma levels increase with obesity, might play an important role in modulating breast cancer cell phenotype. Functional crosstalk occurring between leptin and different signaling molecules contribute to breast carcinogenesis. In this study, we show, in different human breast cancer cell lines, that leptin enhanced the expression of a chaperone protein Hsp90 resulting in increased HER2 protein levels. Silencing of Hsp90 gene expression by RNA interference abrogated leptin-mediated HER2 up-regulation. Leptin effects were dependent on JAK2/STAT3 activation, since inhibition of this signaling cascade by AG490 or ectopic expression of a STAT3 dominant negative abrogated leptin-induced HER2 and Hsp90 expressions. Functional experiments showed that leptin treatment significantly up-regulated human Hsp90 promoter activity. This occurred through an enhanced STAT3 transcription factor binding to its specific responsive element located in the Hsp90 promoter region as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Analysis of HER2, Akt and MAPK phosphorylation levels revealed that leptin treatment amplified the responsiveness of breast cancer cells to growth factor stimulation. Furthermore, we found that long-term leptin exposure reduced sensitivity of breast cancer cells to the antiestrogen tamoxifen. In the same experimental conditions, the combined treatment of tamoxifen with the Hsp90 inhibitor 17-AAG completely abrogated leptin-induced anchorage-independent breast cancer cell growth. In conclusion, our results highlight, for the first time, the ability of the adipocyte-secreted factor leptin to modulate Hsp90/HER2 expressions in breast cancer cells providing novel insights into the molecular mechanism linking obesity to breast cancer growth and progression.
- "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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