Role of AIB1 for tamoxifen resistance in estrogen receptor-positive breast cancer cells.

The p160 nuclear receptor coactivator, AIB1 (amplified in breast cancer 1), is frequently overexpressed in human breast cancer and has been shown to be associated with tamoxifen resistance. The present study aimed to investigate the role of AIB1 in tamoxifen resistance of breast cancer cells. We reconstructed the RNA interference expression vector, pGenesil-1-U6, specially targeting AIB1 mRNA, and it was stably transfected into the human breast cancer cell line BT474. Cell proliferation and cell cycle distribution were assessed in the cells transfected with scramble control shRNA (BT474/shControl) and AIB1 shRNA (BT474/shAIB1) to explore the possible functions of AIB1 in breast cancer progression. The expression of AIB1, ERalpha, HER2 and pS2 was analyzed in the presence of 17beta-estradiol or 4-hydroxytamoxifen (Tam) by Western blot analysis. Compared with the parental BT474 and the BT474/shControl cells, the levels of AIB1 mRNA and protein were significantly reduced in BT474/shAIB1 cells. A knockdown of AIB1 levels restored the inhibitory effect of tamoxifen on cell proliferation. Tam behaves like an estrogen agonist in ER-positive breast cancer cells that express high levels of AIB1 and HER2, resulting in de novo resistance. Knockdown of AIB1 can eliminate this cross talk and restore the antitumor effects of tamoxifen.

Su Q ，Hu S ，Gao H ，Ma R ，Yang Q ，Pan Z ，Wang T ，Li F ... -  《-》

Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence.

Mc Ilroy M ，Fleming FJ ，Buggy Y ，Hill AD ，Young LS ... -  《-》

Amplified in breast cancer 1 in human epidermal growth factor receptor - positive tumors of tamoxifen-treated breast cancer patients.

Kirkegaard T ，McGlynn LM ，Campbell FM ，Müller S ，Tovey SM ，Dunne B ，Nielsen KV ，Cooke TG ，Bartlett JM ... -  《CLINICAL CANCER RESEARCH》

Epidermal growth factor receptor (EGFR) and the estrogen receptor modulator amplified in breast cancer (AIB1) for predicting clinical outcome after adjuvant tamoxifen in breast cancer.

Dihge L ，Bendahl PO ，Grabau D ，Isola J ，Lövgren K ，Rydén L ，Fernö M ... -  《BREAST CANCER RESEARCH AND TREATMENT》

A metastatic breast tumor cell line, GI-101A, is estrogen receptor positive and responsive to estrogen but resistant to tamoxifen.

The progression of human breast cancer is often associated with a loss of estrogen dependence for growth, a resistance to estrogen antagonists such as tamoxifen, and the metastatic spread of the disease to secondary sites. Cell lines developed from such advanced breast tumors are often metastatic in athymic mice, show a loss of estrogen receptor mRNA and protein (ER-), and do not respond to 17beta-estradiol. However many advanced human breast tumors do express significant amounts of ER transcript, especially when analyzed by more sensitive methods of detection including RT-PCR and Ribonuclease Protection Assay (RPA). No metastatic, ER+breast tumor cell line has previously existed to examine the role of ER in metastatic progression and acquired drug (tamoxifen) resistance. The GI-101A cell line was recently developed from a metastatic breast tumor xenograft and is both tumorogenic and metastatic to the lungs and lymph node when injected into athymic mice, a pattern similar to that seen in patients. While Western blot analysis initially indicated that GI-101A was ER-, analysis of ER mRNA by RT-PCR and RPA have demonstrated the expression of ER (as well as EGF receptor and neu oncogene) transcripts. Functional ER in GI-101A was confirmed by a clear growth response to 17beta-estradiol in culture. Optimal 17beta-estradiol concentrations were significantly lower for GI101A than for MCF-7 (1 n m as opposed to >/=10 n m), and GI-101A growth was inhibited at 17beta-estradiol concentrations above 10 n m. Unlike MCF-7 cells, GI-101A shows constitutive expression of pS2 protein in hormone depleted media with no apparent induction by 17beta-estradiol supplimentation, as well as a resistance to the anti-estrogen tamoxifen at concentrations up to 10 n m. Finally, ER transcripts which likely represent an alternately spliced ER variant which has previously been shown to encode a constitutively active ER protein have been detected in GI-101A at levels similar to the wild type transcript, and offer a possible mechanism for estrogen independence, tamoxifen resistance, and constitutive pS2 expression.

Morrissey JJ ，Raney S 《CELL BIOLOGY INTERNATIONAL》