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

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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.