Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)-mediated approaches significantly reversed the tamoxifenresistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis.Implications: These findings identify RRM2 as an AKT-regulated gene, which plays a role in tamoxifen resistance and may prove to be a novel target for effective diagnostic and preventative strategies. Mol Cancer Res; 12(3); 394-407. Ó2013 AACR. IntroductionBreast cancer is the most common cancer in American women with an estimated 232,340 new cases of invasive and 64,640 new cases of noninvasive breast cancer this year alone. In 2013, 39,620 women were expected to die from breast cancer, and about 1 in 8 U.S. women would develop invasive breast cancer over the course of her lifetime (1). Breast cancer is frequently classified on the basis of hormone receptor status where 60% of premenopausal and 75% of postmenopausal cancers are estrogen receptor-positive (ER þ ; ref. 2). The ER acts as a master regulator of gene expression in breast cancer and promotes tumor progression via upregulating genes for proliferation and cell survival

Drug resistance is a fundamental problem in cancer chemotherapy. Intracellular calcium concentration ([Ca2+]i) may play a role in the development of chemoresistance. We investigated the regulatory role of [Ca2+]i in Taxol resistance in the non‐small‐cell lung cancer cell line A549 and its chemoresistant subclone A549‐T24. Measurement of cytosolic calcium ([Ca2+]c) in single cells and cell populations revealed similar levels of basal calcium in the two cell lines. However, a reduced response to thapsigargin (a sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) inhibitor) in A549‐T24 cells compared to the parent cell line suggested a lower ER Ca2+ content in these cells. mRNA expression of SERCA2b and SERCA3, major Ca2+ pumps involved in ER Ca2+ homeostasis, did not significantly differ between the two cell lines, as revealed by RT–PCR. An altered calcium influx pathway in the Taxol‐resistant cell line was observed. Modulation of the ER calcium pools using CMC (4‐chloro‐m‐cresol) and ATP revealed lower ryanodine receptor (RyR) and IP3 receptor (IP3R)‐sensitive Ca2+ stores in the chemoresistant cell line. Western blot and RT–PCR studies suggested that A549‐T24 cells expressed higher levels of the antiapoptotic protein Bcl‐2 and the calcium‐binding protein sorcin, respectively, in comparison to the parent cell line. Both of these proteins have been previously implicated in chemoresistance, in part, due to their ability to modulate [Ca2+]i. These results suggest that altered intracellular calcium homeostasis may contribute to the Taxol‐resistant phenotype. British Journal of Pharmacology (2004) 142, 305–316. doi:

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These results suggest that the partial pressure of oxygen in the anterior chamber is sensitive to the environment in contact with the cornea. In the rat eye, the delivery of oxygen to the anterior chamber via transcorneal diffusion may be more significant than for larger animals.

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