A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer

Abstract

Breast cancer is the most common cancer and the deadliest among women worldwide. Estrogen signaling is closely associated with hormone-dependent breast cancer (estrogen and progesterone receptor positive), which accounts for two-thirds of tumors. Hormone therapy using antiestrogens is the gold standard, but resistance to these treatments invariably occurs through various biological mechanisms, such as changes in estrogen receptor activity, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle dysregulations. All these factors have led to the development of new therapies, such as selective estrogen receptor degraders (SERDs), or combination therapies with cyclin-dependent kinases (CDK) 4/6 or PI3K inhibitors. Therefore, understanding the estrogen pathway is essential for the treatment and new drug development of hormone-dependent cancers. This mini-review summarizes current literature on the signalization, mechanisms of action and clinical implications of estrogen receptors in breast cancer.

Keywords: breast cancer; endocrine resistance; estrogen receptor.

Figure 1

Risk factors of breast cancer. Genetic as well as environmental factors participate in breast cancer development. ATB: antibiotics; BPA: bisphenol A; DTT: dichlorodiphenyltrichloroethane; HRT: hormonal replacement therapy; NSAID: non-steroidal anti-inflammatory drugs; PAH: polycyclic aromatic hydrocarbons; PCB: polychlorinated biphenyls.

Figure 2

Main signaling pathways leading to cell proliferation and survival following growth factor receptors stimulation. Growth factor receptors stimulation by EGF or IGF1 for example activates signaling pathways involving notably Ras/MAPK/ERK or PI3K/AKT/mTOR, leading to transcription factors activation for the regulation of cell fate. The activation of AKT by PI3K involves PIP2 phosphorylation, which is inhibited by PTEN. CaMK: Ca²⁺/calmodulin-dependent protein kinase; EGF: epidermal growth factor; IGF1: insulin like growth factor 1; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; PIP: phosphatidylinositol phosphate; PKC: protein kinase C; PLC: phospholipase C; PTEN: phosphatase and tensin homolog; S6K1: S6 kinase 1.

Figure 3

Genomic and non-genomic activities of ERα. ERα activation upon estrogen binding (E2) or after its phosphorylation (P) by cellular kinases following growth factor (GF) receptor stimulation leads to its translocation into the nucleus. There, ERα homodimer binds DNA either directly or indirectly, through estrogen responsive elements (EREs), or upon binding to other transcription factors such as AP1 or SP1 that bind DNA through serum responsive elements (SREs). This is the so-called genomic action of ERα which leads to the regulation of the transcription of target genes. ERα can also be anchored to the membrane and interacting with G proteins (Ga) or GF receptors. ERα activation is then implicated in second messenger production (cyclic adenosine monophosphate, cAMP) and signaling pathways stimulation involving PI3K/AKT or Ras/MAPK for example. This nongenomic activity of ERα eventually leads to transcription factors (TFs) activation involved in the regulation of cell proliferation and survival. cAMP: cyclic adenosine monophosphate; E2: estrogen; ERα: estrogen receptor alpha; ERE: estrogen responsive element; Ga: G alpha protein; GF: growth factor; HSP: heat shock protein; MAPK: mitogen-activated protein kinase; P: phosphate; PI3K: phosphoinositide 3-kinase; SRE: serum responsive element.