Rewiring of the Endocrine Network in Triple-Negative Breast Cancer

Abstract

The immunohistochemical definition of estrogen/progesterone receptors dictates endocrine feasibility in the treatment course of breast cancer. Characterized by the deficiency of estrogen receptor α, ERα-negative breast cancers are dissociated from any endocrine regimens in the routine clinical setting, triple-negative breast cancer in particular. However, the stereotype was challenged by triple-negative breast cancers' retained sensitivity and vulnerability to endocrine agents. The interplay of hormone action and the carcinogenic signaling program previously underscored was gradually recognized along with the increasing investigation. In parallel, the overlooked endocrine-responsiveness in ERα-negative breast cancers attracted attention and supplied fresh insight into the therapeutic strategy in an ERα-independent manner. This review elaborates on the genomic and non-genomic steroid hormone actions and endocrine-related signals in triple-negative breast cancers attached to the hormone insensitivity label. We also shed light on the non-canonical mechanism detected in common hormone agents to showcase their pleiotropic effects.

Keywords: endocrine responsiveness; endocrine strategy; steroid hormone; steroid hormone receptor; triple-negative breast cancer.

Figure 1

Potential modes of genomic and non-genomic approaches of (A) estradiol and (B) progesterone, which cooperated in regulating the carcinogenesis process. cGMP, cyclic guanosine monophosphate; EGF, epidermal growth factor; ER, endoplasmic reticulum; MAPK, mitogen-activated protein kinase; NFAT1, nuclear factor of activated T cell; OXPHOS, oxidative phosphorylation; PGC1, proliferator activated receptor-gamma co-activator 1; PKC, protein kinase C; PRE, progesterone reactive element; TAM, tamoxifen.

Figure 2

Model of androgen-induced genomic and non-genomic actions in TNBC cells. Classical AR was divorced from the HSP and formed the homodimer once activated by a ligand, which was then transferred into nuclear actions and binding to the promotor of ESR2 gene linked to regulation of ERβ expression. Further, the expressed ERβ dimerized with AR then impeded the nuclear translocation of AR-AR homodimer and thus blocked downstream oncogenic signaling. In addition, androgen stimulation activated the classical AR/Src complex assembly, rapidly recruiting PI3K and FAK, which triggered the downstream phosphorylation and the consequent cytoskeleton changes. Besides, the G protein-coupled form of AR activated downstream MAPK/MEK/ERK signaling and induced the phosphorylation of cAMP and PKA. ARE, androgen receptor element; Egr-1, early growth response 1; GRCP, G protein coupled receptor; HSP, heat shock protein; ZEB1, zinc finger E-box binding homeobox 1.