A major limitation of endocrine therapies targeting estrogen receptor ? (ER?) is the development of acquired resistance to therapies such as tamoxifen in initially responsive patients. Altered microRNA expression plays a role in endocrine resistance; however, little is known about what regulates microRNA in breast cancer. This exploratory study addresses PA- 16-177 ?Role of RNA modifications in cancer biology (R21) Question 1: ?What are the cancer- associated alterations in readers, writers, and erasers of reversible RNA modifications?? Here, we will address the role of the RNA methylation reader Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) in tamoxifen-resistant breast cancer. The rationale for our proposed experiments is that increased N(6)-methyladenosine (m6A) in primary-microRNAs (pri-miRNAs) was associated with increased levels of the corresponding mature miRNA in a triple negative breast cancer cell line. HNRNPA2B1 is a reader of the m6A mark in pri-miRNAs and interacts directly with DGCR8 (a component of the DROSHA complex in the nucleus) to promote processing of pri-miRNAs to precursor-miRNAs (pre-miRNAs). We present preliminary data showing that HNRNPA2B1 is increased in tamoxifen-resistant, ER?+ LCC9 cells derived from tamoxifen-sensitive, ER?+ MCF-7 breast cancer cells. Using online data, we found that high HNRNPA2B1 transcript levels in primary breast tumors are associated with reduced overall survival. A new report showed increased HNRNPA2B1 in breast tumor specimens and cell lines. The proposed experimental plan addresses the hypothesis that HNRNPA2B1 overexpression stabilizes pri-miRNAs that promote endocrine resistance.
For 2017, the American Cancer Society estimates that 252,710 US women and 2,470 men will be diagnosed with invasive breast cancer and 41,070 women will die from disease metastases. The major goals of this exploratory project are to determine if HNRNPA2B1, a reader of N(6)methyladenosine in miRNA, 1) drives tamoxifen/endocrine resistance and 2) is a possible marker for resistance in primary breast tumors.