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

三阴性乳腺癌(TNBC)是一种雌激素缺乏的乳腺癌亚型 受体(ER)和孕激素受体(PR)表达及HER2扩增/过表达。它 是一个重大的临床挑战，因为TNBC患者的预后很差，而且 占公元前死亡人数的不成比例。尽管包括PARP抑制剂在内的靶向治疗 而trop-2导向的抗体(Ab)药物结合物以及免疫疗法(抗PD-1/PD-L1抗体)具有 已被批准用于治疗晚期/转移性TNBC，化疗目前仍是大 对部分TNBC患者和初见成效。然而，耐药和肿瘤复发频繁发生， 提示TNBC具有高度的异质性，迫切需要开发更有效的分子生物学。 这种侵袭性疾病的基础疗法。我们最近发现HER3(或 在所检测的大约一半的TNBC临床样本和细胞系中存在ErbB3)。TCGA的生物信息学分析 数据集显示，在TNBC中，erbB3的高表达与较差的预后显著相关 患者，特别是具有Basal-like 1(BL1)、Lumina-雄激素受体(LAR)或 基底样2(BL2)。然后我们确定了PHF8(PhD Finger Protein 8，或KDM7B，一种组蛋白赖氨酸去甲基酶) 作为在BL2-TNBC细胞系中沉默erbB3的最下调的表观遗传修饰物之一。这个 通过对BC临床标本和细胞的分析，进一步支持了erbB3和PHF8的正相关 台词。此外，功能获得和功能丧失方法的研究表明，PHF8发挥了 在HER3介导的促进BL1/2-TNBC细胞生长、迁移和侵袭中起关键作用。因此，我们 假设PHF8在BL1/2-TNBC中作为HER3信号的关键下游介体 进展和转移；抑制HER3或PHF8将显著增强肿瘤的疗效 针对TNBC的化疗。我们打算定义HER3信号转导的分子基础 PHF8在TNBC和随后的肿瘤进展和转移中的上调，并确定 HER3或PHF8灭活联合化疗对TNBC的治疗潜力

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.