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

By Tyler E. Miller, K. Ghoshal, B. Ramaswamy, Satavisha Roy, J. Datta, C. Shapiro, S. Jacob, S. Majumder. Journal of Biological Chemistry, 2008

780 citations recorded by the source corpus.

We explored the role of microRNAs (miRNAs) in acquiring resistance to tamoxifen, a drug successfully used to treat women with estrogen receptor-positive breast cancer. miRNA microarray analysis of MCF-7 cell lines that are either sensitive (parental) or resistant (4-hydroxytamoxifen-resistant (OHTR)) to tamoxifen showed significant (>1.8-fold) up-regulation of eight miRNAs and marked down-regulation (>50%) of seven miRNAs in OHTR cells compared with parental MCF-7 cells. Increased expression of three of the most promising up-regulated (miR-221, miR-222, and miR-181) and down-regulated (miR-21, miR-342, and miR-489) miRNAs was validated by real-time reverse transcription-PCR. The expression of miR-221 and miR-222 was also significantly (2-fold) elevated in HER2/neu-positive primary human breast cancer tissues that are known to be resistant to endocrine therapy compared with HER2/neu-negative tissue samples. Ectopic expression of miR-221/222 rendered the parental MCF-7 cells resistant to tamoxifen. The protein level of the cell cycle inhibitor p27Kip1, a known target of miR-221/222, was reduced by 50% in OHTR cells and by 28–50% in miR-221/222-overexpressing MCF-7 cells. Furthermore, overexpression of p27Kip1 in the resistant OHTR 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7f62fe90787e09d25c7e56f2b44be76168bf8bf4

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Citations in the corpus

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “Beside chemotherapy, microRNAs can also improve the responsiveness to targeted therapies: overexpression of miR-221 and miR-222 is responsible for resistance to anti-estrogenic therapies, as Tamoxifen (Miller et al, 2008; Zhao et al, 2008), and Fulvestran (Rao et al, 2011), whereas ectopic expressio”
MicroRNA: Biogenesis, Function and Role in Cancer (2010, background): “MiRNA signature profiles can be used to determine prognosis [338340], response to drug therapy [341], predict treatment efficiency [342, 343], race susceptibility [23] and patient susceptibility to cancer and metastasis [344-346].”
MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy (2011, positive): “Similar findings were identified for miR-342, which was downregulated in tamoxifen-resistant cells; overexpression sensitized cells to tamoxifen-induced apoptosi”
MicroRNAs in development and disease. (2011, background): “On the other hand, miRNAs that regulate the ER include miR-206 (3) and miR-221/222 (3), which is consistent with the finding that miR-221/222 is upregulated in tamoxifen-resistant cancer cells (427).”
Biological determinants of endocrine resistance in breast cancer (2009, background): “The microRNAs (miRNAs) miR-221 and miR-222 reduce p27 expression and confer resistance to tamoxifen, although the precise mechanism of resistance is unclear, as these miRNAs also reduce ERα expression and are overexpressed in ERBB2-overexpressing breast cancer”