Although endocrine therapies that block the production or subsequent effects of estrogen have been a bedrock of the treatment for hormonally driven breast cancer for more than 40 years, resistance poses a major threat to their efficacy and has become a focus of ongoing research.
Mutations in the ESR1
gene that encodes estrogen receptor alpha (ERα) have emerged as a central mechanism of resistance thought to be acquired because of the selective pressures of endocrine therapy, particularly with aromatase inhibitors (AIs).
As a result of the technological advances that have yielded the development of liquid biopsies, monitoring the presence of ESR1
mutations in circulating tumor DNA (ctDNA) has the potential to change practice by enabling the early detection of tumor progression and guiding therapeutic decisions.
Despite gaps in current knowledge, investigators are already working toward the development of novel treatment strategies to combat the effects of the mutations and wrestle back control of ER-positive tumor growth.
As the cellular orchestrator of the effects of the estrogen hormones, ERs play an important role in a plethora of processes, including its most renowned functions in reproduction and sexual development and in modulating the immune system.1,2
Figure. Key Components of Estrogen Receptor Signaling
Estrogens are steroid hormones that pass freely across the cell membrane and do not need to bind to a membrane-bound receptor to transmit their signal into the cell. Although they can be found in the membranes, ERs predominantly reside in the nucleus, where, after binding to an estrogen ligand, they can act directly as a transcription factor.
An ER molecule is made up of a number of domains; at either end is a transcriptional activation domain, one activated independently of ligand binding (AF-1) and the other ligand-dependent (AF-2). These flank the ligand-binding domain (LBD) and the DNA-binding domain (Figure A
Following ligand binding at the LBD, 2 ER molecules pair up and are phosphorylated. This allows the estrogen-ER complex to interact with various corepressors or coactivators, which determine its activation state.
Activated ERs subsequently bind to specific sites within the nuclear DNA, known as estrogen response elements (EREs), found in the promoter region of target genes. In this way, the ER both directly (as a transcription factor) and indirectly (through activation of other transcription factors) activates sets of genes that regulate the proliferation, differentiation, and survival of cells in which it is expressed (Figure B
ER-Driven Breast Cancer
ER signaling has been shown to be indispensable to mammary gland development,6,7
although the precise mechanisms through which it regulates the proliferation and differentiation of human breast cells is unclear. A relatively small number of cells in the normal mammary gland express ERs.8
There are 2 types of ERs: ERα and ER beta (ERβ). Increased expression of ERα is observed in breast cancers and can be seen from the earliest stages of tumorigenesis,9
suggesting that dysregulated ER signaling plays an important role in breast tumor formation. ERβ mediates many of estrogen’s effects on breast tissue.10
Expression of ERα is observed in around 70% of breast cancers and, as such, ER-positive tumors make up the largest subgroup of breast cancers.11,12
The proportion of patients with ER positivity increases with age; in postmenopausal women, breast cancers are overwhelmingly ER-positive.13
Efforts to treat hormonally driven breast cancers have led to endocrine therapies that are designed to either prevent the production of estrogen or block its effects on the ER. There are 3 classes of endocrine therapy: selective ER modulators (SERMs), selective ER downregulators (SERDs), and AIs.
SERMs are nonsteroidal compounds that bind to the ER and can act as either an agonist or antagonist depending on a number of tissue-specific and other factors. This class of agents includes tamoxifen, which in 1977 became the first FDA-approved antihormonal therapy for breast cancer. As a result of its agonist effects in certain tissues, tamoxifen is associated with adverse events (AEs) with longterm use, such as an increased risk of endometrial cancer and thrombotic events.14
Several novel SERMs have been developed with reduced agonist activity, including raloxifene, which has significantly less of an impact on endometrial cells in preclinical models.14