Role of P4HA1 in Endocrine Resistance of Breast Cancer

P4HA1在乳腺癌内分泌抵抗中的作用

基本信息

批准号：
10571404
负责人：
GaoFeng Xiong
金额：
$ 22.95万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2023-09-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10571404
关键词：
4-Hydroxy-Tamoxifen Binding Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cells Clinical Collagen Data Disease Progression Drug Combinations Endocrine Endoplasmic Reticulum Enzymes Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Fulvestrant Goals Hydroxylation Hydroxyproline Investigation Malignant Neoplasms Molecular Pathway interactions Patient-derived xenograft models of breast cancer Peptides Proline Proteins Reactive Oxygen Species Recurrence Regimen Regulation Relapse Resistance Role Sampling Selective Estrogen Receptor Modulators Stress Tamoxifen Testing Therapeutic Xenograft Model acquired treatment resistance cancer cell clinical practice combinatorial endoplasmic reticulum stress experimental study hormone therapy in vivo inhibitor knock-down malignant breast neoplasm mortality new therapeutic target novel overexpression patient derived xenograft model protein expression therapeutic target therapy resistant tumor tumor growth

项目摘要

Abstract: Tamoxifen is the oldest and the most widely used selective estrogen receptor modulators. Fulvestrant is a selective estrogen receptor down-regulator which blocks and damages estrogen receptors. Fulvestrant is introduced to clinical as second-line therapy post disease progression after tamoxifen. Endocrine treatment is the first-line therapy for estrogen receptor positive breast cancer patients. However, 30%-50% of the breast cancer patients with five to ten years of treatment acquire resistance to endocrine therapy. Resistance to endocrine therapy and recurrence is the leading cause of mortality in breast cancer patients. Prolyl hydroxylation (P4H), is an enzyme hydroxylates proline into 4-hydroxyproline of collagens and other proteins with the -X-Pro- Gly- sequences as collagens in the endoplasmic reticulum. P4HA1, the alpha subunit of P4H1, is responsible for both peptide binding and catalytic activity. In this study, we found that increased expression of P4HA1 was detected in endocrine therapy resistant luminal breast cancer cells compared with endocrine therapy sensitive cells. High P4HA1 expression significantly correlates with short relapse-free survival in luminal breast cancer patients. Inactivation of P4HA1 protein sensitized endocrine resistance luminal cancer cells to 4- Hydroxytamoxifen (4OHT) or fulvestrant treatment, accompanied by increased reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. These preliminary data indicate that P4HA1 is an important regulator for endocrine resistance of breast cancer. We hypothesize that inhibition of P4HA1 sensitizes luminal breast cancer cells to endocrine therapy by inducing ROS-ER stress pathway. To investigate the importance of P4HA1 for endocrine resistance, we will introduce P4HA1 protein expression in endocrine sensitive luminal breast cancer cell lines. We will examine resistance to 4OHT or fulvestrant treatment, ER stress level, as well as ROS levels in P4HA1-overexpression cells under 4OHT or fulvestrant treatment. We will perform rescue experiments in P4HA-silenced endocrine resistant cells using ROS inhibitor. For the in vivo study, we will use endocrine resistant luminal breast cancer cell lines orthotropic xenograft model, and resistance luminal breast cancer patient- derived-xenograft (PDX) models. We will determine whether inactivation of P4HA1 renders these endocrine resistant tumors sensitive to tamoxifen or fulvestrant treatment in vivo, and examine whether the overwhelmed ER stress and ROS levels are associated with endocrine sensitivity in tumors. In summary, this investigation will uncover a novel uncanonical role of P4HA1 in endocrine resistance by regulation ROS-ER stress pathway, and explore P4HA1 as a novel therapeutic target for combinatorial therapy for endocrine resistant luminal breast cancer patients.

抽象的：他莫昔芬是最古老，使用最广泛的选择性雌激素受体调节剂。 Fulvestrant是一个选择性雌激素受体下调，可阻止和损害雌激素受体。 Fulvestrant是在他莫昔芬后，疾病进展后作为二线治疗引入临床。内分泌治疗是雌激素受体阳性乳腺癌患者的一线治疗。但是，乳房的30％-50％五到十年治疗的癌症患者对内分泌疗法具有抗药性。抵抗内分泌疗法和复发是乳腺癌患者死亡率的主要原因。羟基羟基化（P4H）是一种羟基羟基盐水蛋白酶，进入4-羟基胶原蛋白和其他蛋白质，并具有-x-pro- Gly-序列作为内质网中的胶原蛋白。 P4HA1是P4H1的α亚基，负责用于肽结合和催化活性。在这项研究中，我们发现P4HA1的表达增加为与内分泌治疗敏感相比，在内分泌疗法抗性腔内乳腺癌细胞中检测到细胞。高P4HA1表达与腔内乳腺癌中无复发生存显着相关患者。 P4HA1蛋白敏化内分泌抗性腔术细胞的灭活对4-- 羟基莫昔芬（4OHT）或氟维治疗，伴随着活性氧（ROS）增加和内质网（ER）应力。这些初步数据表明P4HA1是用于内分泌对乳腺癌的抗性。我们假设抑制P4HA1使腔乳腺癌敏感细胞通过诱导ROS-ER应激途径来进行内分泌治疗。调查P4HA1的重要性内分泌耐药性，我们将在内分泌敏感的腔内乳腺癌中引入P4HA1蛋白表达细胞系。我们将检查对4OHT或FULVESTRANT治疗，ER应力水平以及ROS水平的耐药性在4OHT或FULVESTRANT处理下的P4HA1超过表达细胞中。我们将在使用ROS抑制剂P4HA脱毛的内分泌耐药细胞。对于体内研究，我们将使用内分泌耐药性腔内乳腺癌细胞系的orthotropic异种移植模型和耐药性腔内乳腺癌患者 - 衍生 - Xenrograpt（PDX）模型。我们将确定P4HA1失活是否会导致这些内分泌对他莫昔芬敏感的耐药性肿瘤或体内拟人治疗，并检查是否不知所措 ER应力和ROS水平与肿瘤中内分泌敏感性有关。总而言之，这项调查将揭示了P4HA1在调节ROS-ER应力途径中的新型非传统作用，并且探索P4HA1作为组合疗法的新型治疗靶标，可用于内分泌乳房癌症患者。