From bench to bedside: What do we know about hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer?

Abstract

Breast cancer is a heterogeneous disease. Thanks to extensive efforts from research scientists and clinicians, treatment for breast cancer has advanced into the era of targeted medicine. With the use of several well-established biomarkers, such as hormone receptors (HRs) (i.e., estrogen receptor [ER] and progesterone receptor [PgR]) and human epidermal growth factor receptor-2 (HER2), breast cancer patients can be categorized into multiple subgroups with specific targeted treatment strategies. Although therapeutic strategies for HR-positive (HR+) HER2-negative (HER2-) breast cancer and HR-negative (HR-) HER2-positive (HER2+) breast cancer are well-defined, HR+ HER2+ breast cancer is still an overlooked subgroup without tailored therapeutic options. In this review, we have summarized the molecular characteristics, etiology, preclinical tools and therapeutic options for HR+ HER2+ breast cancer. We hope to raise the attention of both the research and the medical community on HR+ HER2+ breast cancer, and to advance patient care for this subtype of disease.

Keywords: ERα; HER2; HR+ HER2+ breast cancer; The crosstalk between ER and HER2.

Fig. 1. The signaling crosstalk between ERα and HER2 in HR+ HER2+ breast cancer

(a) ERα binds to estrogen and gets activated in the cytoplasm. After activation, ERαs dimerize and are translocated into the nucleus, where they bind to the estrogen response element (ERE) on ERα target genes. The recruitment of coactivators (CoA) and corepressors (CoR) to ERα facilitates the transcriptional activity of ERα. The activated ERα induces the expression of growth factor receptor ligands, such as TGFα and amphiregulin, and membrane tyrosine receptor kinases (e.g., HER1 and HER2) to augment the activity of the HER2 signaling pathway. (b) The non-genomic action of ERα occurs transiently outside the nucleus. The estrogen-activated ERα in the plasma membrane and/or cytosol can interact with and activate HER2, and subsequently activate a downstream signaling cascade. In addition, the overexpression of HER2 sequesters ERα in the cytosol, which augments the non-genomic activity of ERα. (c)The downstream signaling output of the HER pathway diverges into two major signaling axes: PI3K/AKT (AKT signaling module) and RAS/RAF/MEK/ERK (MAPK signaling module). These two signaling pathways are involved in cell proliferation and survival. The activation of the AKT and MAPK signaling modules phosphorylates and activates ERα. Furthermore, the activation of ERK can enhance the function of CoAs (e.g., AIB1) but diminish the function of CoRs (e.g., SMRT).