MicroRNA-221/222 Confers Tamoxifen Resistance in Breast Cancer by Targeting p27Kip1

Abstract

Kip1 in the resistant OHT R cells caused enhanced cell death when exposed to tamoxifen. This is the first study demonstrating a relationship between miR-221/222 expression and HER2/neu overexpression in primary breast tumors that are generally resistant to tamoxifen therapy. This finding also provides the rationale for the application of altered expression of specific miRNAs as a predictive tamoxifen-resistant breast cancer marker.Breast cancer is the most common malignancy in women, accounting for 31% of all female cancers. An estimated 178,480 new cases of invasive breast cancer was diagnosed in the United States in 2007, and 40,460 women will die of this cancer. Over two-thirds of breast cancers exhibit high concentrations of estrogen receptor, which contribute to tumor growth and progression. Blocking the steroid hormone pathway with tamoxifen and/or oophorectomy has been shown to be effective in this patient population. The Early Breast Cancer Trialists' Collaborative Group overview demonstrated a significant improvement in 15-year survival with the addition of adjuvant tamoxifen for 5 years following surgery (1). Furthermore, tamoxifen can also reduce the incidence of contralateral breast cancer and has been approved as a prophylactic agent to prevent breast cancer. Despite this accomplishment in the management of women with potentially endocrine-responsive breast cancers, a significant proportion of these women will experience disease progression due to either an intrinsic or acquired resistance to tamoxifen.Nongenomic activation of epidermal growth factor receptor/ HER2 signaling by tamoxifen is an important factor contributing to tamoxifen resistance. This leads to activation of both the p42/44 mitogen-activated protein kinase (MAPK) and Akt signaling pathways, which favor cell proliferation and survival. These changes could be blocked by the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitnib, suggesting that epidermal growth factor receptor/HER2 signaling is directly involved in tamoxifen resistance (2). The preclinical data are corroborated by clinical observations that tumors expressing HER2 exhibit poor outcome when treated with tamoxifen (3). None of the molecular mechanisms proposed for tamoxifen resistance (for review, see Ref. 4) have led to the development of a gene expression profile that can consistently identify resistant tumors and benefit these patients from upfront use of alternative drugs such as aromatase inhibitors.Recent studies have highlighted the key regulatory roles of microRNAs (miRNAs) 3 in all fundamental cellular processes in animals and plants. Altered expression of miRNAs in primary human cancers has been used for tumor diagnosis, classification, staging, and prognosis (5). These small noncoding RNAs regulate expression of their target proteins primarily by inhibiting translation of the target mRNA and in some cases by inducing rapid decay of the message (6). A study with 76 neo-* This work was supported, in whole or in part, by National Institut...

Widespread Estrogen-Dependent Repression of microRNAs Involved in Breast Tumor Cell Growth

“…We observed a marked increase in the expression of several miRNAs (miR-21, miR-181b, miR-26a, miR-26b, miR-27b, miR-23b) upon antiestrogen treatment. Interestingly, several of these miRNAs (miR-21, miR-23b, miR-181b) were shown as being differentially expressed in tamoxifen-resistant MCF-7 (39). Therefore, the analysis of the expression of these candidate miRNAs in larger cohorts may certainly warrant further investigation to help in the evaluation of the response to hormonal therapy.…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…42 However, the miR-221/222 cluster is associated with tamoxifen resistance in breast cancer cells. 43,44 Miller et al 45 reported that miR-221/222 expressions were upregulated in endocrine therapy-resistant luminaltype breast cancer cells. MiR-221/222 are negative regulators of p27 kip1 , a cell cycle inhibitor and tumor suppressor, [46][47][48][49][50] and upregulated expressions of these miRNAs and significant reductions in p27 kip1 levels have been reported in tamoxifen-resistant breast cancer cells; therefore, miR-221/222 might regulate tamoxifen sensitivity via the direct targeting of p27 kip1 .…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…miR-221/222 are overexpressed in fulvestrant-resistant breast cancer cells and are associated with the acquisition of fulvestrant resistance [113] . Furthermore, up-regulation of miR-221/222 in breast cancer cells also causes tamoxifen resistance by targeting p27 [114] . miR-221/222 is a promising candidate for breast cancer with chemoresistance.…”