Posttranslational Regulation of FOXA1 in Breast Cancer

FOXA1 在乳腺癌中的翻译后调控

• 批准号: 10978823
• 负责人: Hector Luis Franco
• 金额: $ 30.6万
• 依托单位: COMPREHENSIVE CANCER CENTER/ UNIV/PR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10978823
• 关键词: Posttranslational; Regulation; FOXA1; Breast; Cancer

Project Summary Breast cancer is the second leading cause of cancer mortality in women and nearly 75% of all breast tumors express estrogen receptor alpha (ER) at the time of diagnosis. Despite the therapeutic successes of endocrine therapies designed to target ER function, about 30-40% of tumors become resistant to endocrine therapy, either through de novo or acquired resistance, and still retain the expression of ER. Herein we propose to study the regulation of FOXA1, a pioneer transcription factor that enables ER binding to chromatin, whose theoretical inhibition would circumvent known mechanisms of endocrine therapy resistance. In breast cancer, FOXA1 is responsible for almost all of the ER binding events in the genome and its upregulation is associated with enhancer reprograming in endocrine resistance. However, there is a paucity of information about how FOXA1 itself is regulated and how cancer cells repurpose its pioneering activities to drive oncogenesis. To this end, our lab has been studying the crosstalk between the endocrine and immune systems in breast cancer. We have discovered that FOXA1, in response to the proinflammatory cytokines, is driven to non- canonical sites across the genome to promote chromatin accessibility for estrogen-liganded ER. These newly formed enhancers were found in compacted/latent regions of the genome and promoted the expression of a novel gene set that was predictive of poor clinical outcomes in patients. Concurrently, we discovered that FOXA1 is post-translationally modified (PTM) in response to proinflammatory cytokines at two evolutionarily conserved amino acids. The post-translational modification of FOXA1 in response to external stimuli has not been shown before and suggests an important mechanism that underlies FOXA1 regulation and function. Therefore, the overall goal of this project is to determine the molecular events that allow proinflammatory signaling to alter endocrine signaling through modulation of FOXA1 function and the biological consequences of this crosstalk. We hypothesize that estrogen- and TNFα-directed PTMs of FOXA1 dictate binding site selection, driving ERα to non-canonical enhancers across the genome, leading to expression programs that underlie the tumorigenesis of breast cancer. To systematically test this hypothesis, will use an integrated set of molecular, genomic, and proteomic approaches to: (Aim 1) define the role of FOXA1 PTMs on its pioneering function and chromatin occupancy, (Aim 2) identify the writers and readers of FOXA1 PTMs, and (Aim 3) understand inflammation- based modulation of FOXA1 independent of PTMs. We will perform these experiments in breast cancer cell lines, ER+ patient-derived xenografts (PDX), and in ER+ mature luminal cells isolated from patient tumors. The dependence on FOXA1 for hormone receptor signaling makes it an attractive therapeutic target. While there are currently no known inhibitors of FOXA1 and its protein structure makes it difficult to target therapeutically, our ability to understand basic molecular mechanisms is directly correlated with our ability to develop better therapeutic interventions. Defining how FOXA1 is regulated becomes key to this endeavor.

项目总结

项目成果

Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers.

男性乳腺癌的单细胞转录和表观遗传学特征提名了明显的癌症特异性增强子。

• DOI: 10.3390/ijms241713053
• 发表时间: 2023-08-22
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Kim, Hyunsoo;Wisniewska, Kamila;Regner, Matthew J.;Thennavan, Aatish;Spanheimer, Philip M.;Franco, Hector L.
• 通讯作者: Franco, Hector L.