Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process.

Abstract:This research aims to develop the English for Disability (EFORD) application, on Android-based learning english media for Visually Impaired students and determine its based this on assessment of matter expert, media expert, special needs teacher and students. The research method adopted in this research is Research and Development (R&D). The development of this application through five phases: (1) Analysis of problems, through observation and interviews. (2) Collecting information as product planning / analysis of the needs of the media as required of blind children. (3) The design phase of products such as the manufacture of flow and storyboard navigation map.(4) Design validation phase form of an expert assessment of the media are developed. (5) testing products phase, such as assessment of the application by blind students. The results of this research is EFORD application which is feasible to be used as english learning media for visual impairment application based on assessment: 1)Media expert its obtained a percentage scored 95%, include for very worthy category, 2)Subject matter, expert its obtained percentage scored 75% include for worthy category and 3) Special needs teacher its obtained a percentage scored 83% include for very worthy category. Upon demonstration, students indicated positive response of ≥ 70% in each indicator. Therefore English learning media with Android based application English for Disability (EFORD) is very feasible to be used as a English learning media especially grammar and speaking english content for students of visual impairment for a number of reasons.

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