No abstract

This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor -positive (ER + ) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER + breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT -induced cell death, but not 4-OHT -induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT-resistant cells selected from ER + breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER + , 4-OHT -resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER + breast cancer.

[1] We analyzed narrow-angle Mars Orbiter Camera (MOC-NA) images to produce highresolution digital elevation models (DEMs) in order to provide topographic and slope information needed to assess the safety of candidate landing sites for the Mars Exploration Rovers (MER) and to assess the accuracy of our results by a variety of tests. The mapping techniques developed also support geoscientific studies and can be used with all present and planned Mars-orbiting scanner cameras. Photogrammetric analysis of MOC stereopairs yields DEMs with 3-pixel (typically 10 m) horizontal resolution, vertical precision consistent with $0.22 pixel matching errors (typically a few meters), and slope errors of 1-3°. These DEMs are controlled to the Mars Orbiter Laser Altimeter (MOLA) global data set and consistent with it at the limits of resolution. Photoclinometry yields DEMs with single-pixel (typically $3 m) horizontal resolution and submeter vertical precision. Where the surface albedo is uniform, the dominant error is 10-20% relative uncertainty in the amplitude of topography and slopes after ''calibrating'' photoclinometry against a stereo DEM to account for the influence of atmospheric haze. We mapped portions of seven candidate MER sites and the Mars Pathfinder site. Safety of the final four sites (Elysium, Gusev, Isidis, and Meridiani) was assessed by mission engineers by simulating landings on our DEMs of ''hazard units'' mapped in the sites, with results weighted by the probability of landing on those units; summary slope statistics show that most hazard units are smooth, with only small areas of etched terrain in Gusev crater posing a slope hazard.