Interaction of GPER-1 with the endocrine signaling axis in breast cancer

Abstract

G Protein-Coupled Estrogen Receptor 1 (GPER-1) is a membrane estrogen receptor that has emerged as a key player in breast cancer development and progression. In addition to its direct influence on estrogen signaling, a crucial interaction between GPER-1 and the hypothalamic-pituitary-gonadal (HPG) axis has been evidenced. The novel and complex relationship between GPER-1 and HPG implies a hormonal regulation with important homeostatic effects on general organ development and reproductive tissues, but also on the pathophysiology of cancer, especially breast cancer. Recent research points to a great versatility of GPER-1, interacting with classical estrogen receptors and with signaling pathways related to inflammation. Importantly, through its activation by environmental and synthetic estrogens, GPER-1 is associated with hormone therapy resistance in breast cancer. These findings open new perspectives in the understanding of breast tumor development and raise the possibility of future applications in the design of more personalized and effective therapeutic approaches.

Keywords: GPER-1; breast cancer; endocrine resistance; estrogen; hypothalamic-pituitary-gonadal axis; personalized medicine.

Figure 1

Overexpression of GPER-1 during Epithelial-Mesenchymal Transition in Breast Cancer. Prolonged exposure to noxious stimuli, such as xenoestrogens or other estrogenic molecules, creates a favorable tumor environment for epithelial-mesenchymal transition in breast cancer cells. This is characterized by increased expression of GPER-1 in the tumor cell, leading to increased activity of signaling pathways dependent on this receptor.

Figure 2

GPER-1 plays a crucial role in the physiological regulation of the HPG axis. GPER-1 is involved in the intricate regulatory network of the hypothalamic-pituitary-gonadal (HPG) axis. The ubiquity of this receptor, both in the central nervous system and in peripheral tissues, determines an integrative role of neuroendocrine and environmental signals. In the hypothalamus and pituitary, GPER-1 modulates the synthesis and pulsatile release of gonadotropins, hormones essential for follicular development, ovulation and spermatogenesis. In the ovaries, GPER-1 mediates the effects of estradiol on cell proliferation, apoptosis and steroid synthesis, thus influencing ovarian function and fertility. The mammary gland, another target tissue of GPER-1, undergoes morphological and functional changes in response to hormonal fluctuations. Disruption of GPER-1 signaling by exposure to estrogenic chemicals or physiological alterations such as menopause can trigger a cascade of events leading to reproductive, metabolic and carcinogenic disorders.