Endocrine therapy – current benefits and limitations

Abstract

Endocrine therapy is a valuable option for the treatment of postmenopausal women with estrogen receptor (ER)-positive breast cancer due to its demonstrated efficacy and favorable safety profile. Although tamoxifen has been the established treatment for more than 20 years its long-term use is associated with several tolerability concerns and may lead to increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to treatment with endocrine agents such as tamoxifen eventually relapse with resistant disease. Sequential use of endocrine therapies is often used in patients as resistance to individual agents develops. Several endocrine approaches have been developed that deprive the tumor of estrogen stimulation, either by directly modulating the ER-signaling pathway or by lowering serum or tumor concentrations of estrogen. In the classic pathway of estrogen signal transduction, the steroid hormone binds to its intracellular ER, triggering a cascade of events that ultimately leads to altered gene transcription. More recently, it has become apparent that ER activation can also occur via estrogen-independent receptor activation or by non-nuclear action through cell surface receptors. Consequently, molecular cross-talk exists between the ER and growth factor signaling cascades, which is a key factor in de novo and acquired resistance to endocrine therapy. Inappropriate activation of growth factor signaling can readily promote endocrine therapy failure in breast cancer cells, either by overriding the growth-inhibitory properties of antiestrogenic drugs or by establishment of a new self-propagating autocrine loop that efficiently drives resistant cell growth. Fulvestrant is a new type of ER antagonist with no agonist effects that binds, blocks and causes degradation of the ER. As multiple signaling pathways are involved in the activation of ER, the use of agents such as fulvestrant that directly target the ER and lead to both degradation of the receptor and abrogation of ER signaling may prevent or delay the development of absolute endocrine resistance. In addition, combining antiestrogenic drugs with inhibitors of cell signaling molecules to target both the ER and growth factor signaling pathways is likely to provide a means of delaying endocrine therapy resistance, leading the way to more effective breast cancer treatment.

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

“…Following EGF pretreatment however, wt PR-B up-shifted in the presence of much lower concentrations of R5020 relative to that observed with R5020 alone (compare lanes 1-4 to lanes 7-10). Additionally, EGF pretreatment of cells expressing wt PR-B resulted in the rapid downregulation of liganded PR in the presence of 0.10 to 10nM R5020 (lanes [10][11][12]. PR transcriptional activity is inversely related to PR stability (16,19); transcriptionally active PR turnover very rapidly and these events appear to be coupled via the phosphorylation of PR Ser294 (14)(15)(16)19).…”

“…In fact, receptor loss or mutation accounts for only 10-20% of clinically observed steroid-hormone resistant breast tumors (10). Thus it has been postulated that in the majority of resistant tumors, control over growth is assumed by locally acting autocrine or paracrine peptide growth factors, and in fact, the invasive cancers with the worst prognosis are those that are growth factor receptor positive and steroid-hormone resistant (11) (12). Growth factors regulate cell growth via the initiation of mitogenic intracellular signal transduction pathways after binding to high-affinity tyrosine kinase receptors on the cell surface, while steroid hormone receptors are ligand-activated transcription factors that can also function as cell membrane-associated signaling molecules (13).…”

Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response

“…The most important ones include the estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). ERpositive tumors are thought to have characteristics of the luminal cell type and are frequently responsive to endocrine treatment (such as tamoxifen or aromatase inhibitors) [4,5]. ER-negative tumors are considered to be more similar to the basal cell type and do not respond to endocrine treatment.…”

Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16Ink4a loss

“…Even so, potent targeted agents impose strong selective pressure that ultimately favors tumor escape, wherein treatment-resistant cancer cells survive and proliferate (3). Indeed, resistance to targeted agents, when not encountered de novo, routinely emerges during treatment (4,5). As a result, targeted agents supplement traditional breast cancer treatment strategies but do not yet obviate the need for surgery, radiation, and cytotoxic chemotherapy.…”