HER3-PHF8 signaling axis in triple-negative breast cancer progression

三阴性乳腺癌进展中的 HER3-PHF8 信号轴

• 批准号: 10584868
• 负责人: Bolin Liu
• 金额: $ 41.67万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-23 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584868
• 关键词: Androgen Receptor; Antibody-drug conjugates; Bioinformatics; Biology; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Cell Growth; Cell Line; Cell Proliferation; Cessation of life; Cisplatin; Clinical; Data; Data Set; Dimerization; Disease; Drug Combinations; Drug resistance; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Epigenetic Process; Estrogen Receptors; Foundations; Genetic Transcription; Goals; Heregulin; Histones; Immunotherapy; In Vitro; Invaded; Ligands; Light; Lysine; Mediating; Mediator; Messenger RNA; Metastatic Neoplasm to the Lung; MicroRNAs; Modeling; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Outcome; PHD Finger; Paclitaxel; Patient-derived xenograft models of breast cancer; Patients; Play; Poly(ADP-ribose) Polymerase Inhibitor; Post-Transcriptional Regulation; Progesterone Receptors; Prognosis; Proteins; Receptor Protein-Tyrosine Kinases; Recurrent tumor; Relapse; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; System; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Up-Regulation; anti-PD-1/PD-L1; anti-PD-L1 antibodies; breast cancer progression; cancer subtypes; chemotherapeutic agent; chemotherapy; effective therapy; gain of function; histone demethylase; in vivo; inhibitor; insight; knock-down; loss of function; malignant breast neoplasm; migration; molecular targeted therapies; neutralizing antibody; novel; novel therapeutics; overexpression; receptor expression; research and development; targeted treatment; therapeutically effective; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

Triple-negative breast cancer (TNBC) is defined as a breast cancer (BC) subtype lack of estrogen receptor (ER) and progesterone receptor (PR) expression and HER2 amplification/overexpression. It represents a significant clinical challenge because the patients with TNBC have a poor prognosis and account for a disproportionate number of BC deaths. Although targeted therapies, including PARP inhibitors and a Trop-2-directed antibody (Ab)-drug conjugate as well as immunotherapy (anti-PD-1/PD-L1 Abs) have been approved to treat advanced/metastatic TNBC, chemotherapy currently remains the mainstay for a large part of TNBC patients and initially effective. However, drug resistance and tumor recurrence frequently occur, suggesting that TNBC is highly heterogenerous and it is in urgent need to develop more effective molecular- based therapies for this aggressive disease. We recently discovered an elevated expression of HER3 (or erbB3) in about half of the TNBC clinical samples and cell lines examined. Bioimformatics analyses of TCGA datasets revealed that high erbB3 expression significantly associated with poorer outcomes in TNBC patients, especially those with the subtypes of Basal-like 1 (BL1), Luminal-Androgen receptor (LAR), or Basal-like 2 (BL2). We then identified PHF8 (PHD finger protein 8, or KDM7B, a histone lysine demethylase) as one of the most downregulated epigenetic modifiers upon silencing of erbB3 in a BL2-TNBC cell line. The positive correlation of erbB3 and PHF8 was further supported via analysis of BC clinical samples and cell lines. Moreover, studies with gain-of-function and loss-of-function approaches indicated that PHF8 played a crucial role in HER3-mediated promotion of BL1/2-TNBC cell growth, migration, and invasion. Thus, we hypothesize that PHF8 functions as a key downstream mediator of HER3 signaling in BL1/2-TNBC progression and metastasis; and inhibition of HER3 or PHF8 will significantly enhance the efficacy of chemotherapy against TNBC. We intend to define the molecular basis of HER3 signaling-mediated upregulation of PHF8 in TNBC and subsequent tumor progression and metastasis, and to determine the therapeutic potential of inactivation of HER3 or PHF8 in combination with chemotherapy against TNBC.

三阴性乳腺癌（TNBC）被定义为缺乏雌激素的乳腺癌（BC）亚型