Novel aspects in endocrine treatment of breast cancer

In recent years substantial improvements in the treatment of hormone responsive primary breast cancer have been achieved by the introduction of aromatase inhibitors (AIs). This demonstrates that withdrawal of estrogen might be superior to antagonism by the selective estrogen receptor modulator (SERM) tamoxifen. Increased efficacy of AIs could be explained by general inhibition of estrogen dependent mechanisms, not only those which are mediated by classical estrogen receptor (ER) that regulate tumor growth.

Two variants of ER, α and ß have been described. There is evidence, that ERα regulates mechanisms in breast cancer cells that promote growth, whereas ERß has inhibitory (i.e. suppressor) functions. Furthermore, a number of ERß subtypes have been characterized. Some of these results from alternative splicing and may have other functions than the primary ERß trascription/translation product. It might be possible to use the inhibitory activity of ERß for breast cancer treatment (e.g. by an activation of ERß mediated suppressor function).

Several studies have demonstrated cross talk between ER related and other signaling pathways such as those activated by Receptor-Tyrosine-Kinases (RTKs e.g. erbB-receptors). MAP-kinases (ERK 1/2) are able to phosphorylate AFI of the ER which might lead to ligand independent activation of ER.

Clinical studies have shown decreased responsiveness to endocrine treatment when ERK1/2 levels are high. RTKs are able to activate coactivators of ER and thereby inhibit corepressors. This might lead to loss of ER dependent cellular responses and reduced susceptibility to tamoxifen or even resistance. HER2-overexpression is likely to be one of the major causes of de novo tamoxifen resistance. Recent studies show evidence for an effective therapeutic approach by designing a combinative targeting adressed to ER/RTK signaling cross talk. It is possible to overcome this resistance by simultaneous treatment of breast cancer with trastuzumab, MAP-kinase inhibitors, RTK (HER2, EGFR) inhibitors or other reagents targeted to RTKs..

Apart from steroid- and growth factor receptors, breast cancer cells express receptors for the hypothalamic peptides gonadotropin releasing hormone (GnRH), growth hormone releasing hormone (GHRH) and somatostatin. GnRH- and somatostatin analogues have minor to moderate inhibitory activity in a number of different tumor cells such as endometrial, ovarian and breast cancer. Cycotoxic hybrids with GnRH analogues and doxorubicin have pronounced inhibitory effects in different breast cancer models. AN-238 is a somatostatin analogue coupled to 2-pyrrolinodoxorubicin. This hybrid leads to inhibition of growth when administered to mice transplanted with mammary tumors that express subtypes 2a, 3 and 5 of somatostatin receptors. GHRH leads to release of growth hormone (GH) from the anterior pituitary gland and subsequently of IGF-1 from the liver. The administration of GHRH antagonists exert their antitumoral activity by reducing the secretion of GH and IGF-1 and direct actions in a number of breast cancer models.

These observations demonstrate that GHRH-antagonists and cytotoxic hybrids containing GnRH or somatostatin are potential candidates for breast cancer treatment.

In summary, individual receptor (signaling) systems (ER, RTK, GnRH, GHRH) act in concert rather than autonomously and thereby exert strong impact both on tumor (cell) growth as well on therapeutic responsiveness. Hence, a profound understanding of the function of receptor systems that goes along with a diagnosis adressing disease and therapeutic relevant biomarkers provide the basis for the optimization and specification of therapeutic approaches based on receptor and/or signaling targeting.

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