Antiestrogen therapy remains one of the most widely used and effective treatments for the management of endocrine responsive breast cancers. This reflects the ability of antiestrogens to compete with estrogens for binding to estrogen receptors. Whereas response rates of up to 70% are reported in patients with tumors expressing estrogen and progesterone receptors, most responsive tumors will eventually acquire resistance. The most important factor in de novo resistance is lack of expression of these receptors. However, the mechanisms driving resistance in tumors that express estrogen and/or progesterone receptors are unclear. A tamoxifen-stimulated phenotype has been described, but seems to occur only in a minority of patients. Most tumors (>80%) may become resistant through other, less well defined, resistance mechanisms. These may be multifactorial, including changes in immunity, host endocrinology, and drug pharmacokinetics. Significant changes within the tumor cells may also occur, including alterations in the ratio of the estrogen receptor alpha:beta forms and/or other changes in estrogen receptor-driven transcription complex function. These may lead to perturbations in the gene network signaling downstream of estrogen receptors. Cells may also alter paracrine and autocrine growth factor interactions, potentially producing a ligand-independent activation of estrogen receptors by mitogen-activated protein kinases. Antiestrogens can affect the function of intracellular proteins and signaling that may, or may not, involve estrogen receptor-mediated events. These include changes in oxidative stress responses, specific protein kinase C isoform activation, calmodulin function, and cell membrane structure/function.

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Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance

Tamoxifen (TAM) has been used in the treatment of breast cancer for over a decade. The observed clinical efficacy of TAM has been attributed to both growth arrest and induction of apoptosis within the breast cancer cells. Although the primary mechanism of action of TAM is believed to be through the inhibition of estrogen receptor (ER), research over the years has indicated that additional, non-ER-mediated mechanisms exist. These include modulation of signaling proteins such as protein kinase C (PKC), calmodulin, transforming growth factor-β (TGFβ), and the protooncogene c-myc. Recent studies, including those from our laboratory, have implicated the role of caspases and mitogen-activated protein kinases (MAPK), including c-Jun N-terminal kinase (JNK) and p38 in TAM-induced apoptotic signaling. Oxidative stress, mitochondrial permeability transition (MPT), ceramide generation as well as changes in cell membrane fluidity may also play important roles in TAM-induced apoptosis. These various signaling pathways underlying TAM-induced apoptosis will be reviewed in this article.

Mechanisms of tamoxifen-induced apoptosis.

Endocrine resistance in breast cancer--An overview and update.

Bcl-2 family-mediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells.

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging.

/pdf/advances-in-estrogen-receptor-biology-prospects-for-3ugewzlna7.pdf

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes

Ki-S1, a marker of proliferation, and bcl-2, the gene product of which is an antagonist of apoptosis, have been measured in 51 ER-positive primary breast cancers before and during tamoxifen treatment and then related to clinical response. Both markers were detected in the majority of tumours before treatment and, quantitatively, initial expression of Bcl-2 protein, but not Ki-S1, was significantly related to the percentage reduction in tumour volume as assessed by ultrasound. Staining for both markers was lower in post treatment samples than in those taken prior to treatments, but concordant decreases in staining indices were seen in only 11 of the 51 tumours. The results demonstrate, using clinical material, that the response to tamoxifen may involve changes in proliferation and/or susceptibility to cell-death.

J C Keen

Papers

Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes

The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer.

Expression of TGFβ isoforms in breast cancer