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Resistance to endocrine therapy in breast cancer

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Abstract

Endocrine therapy is the treatment of choice for patients with breast cancer expressing estrogen receptor (ER) and/or progesterone receptor. The efficacy of endocrine therapy is well established in the prevention, adjuvant and metastatic settings. However, either de novo or acquired resistance is frequently observed. Much effort has been made to elucidate the mechanisms of action underlying resistance to endocrine therapy in breast cancer, and several possible explanations have been suggested. Our previous studies have indicated that combined treatment with an antiestrogen, fulvestrant, and an inhibitor of the HER2 signaling pathway, trastuzumab, or an inhibitor of the HER1 signaling pathway, gefitinib, leads to an additive antitumor effect in breast cancer cells expressing ER and HER2 or HER1, respectively. It has also been suggested that the HER1 or HER2 signaling pathway is upregulated during the development of antiestrogen-resistant growth in breast cancer cells. These findings suggest that signal transduction inhibitors are effective for the treatment of antiestrogen-resistant breast cancer. A hypoxic microenvironment has been shown to promote malignant progression in cancer cells. Our previous study and others have suggested that hypoxia posttranscriptionally reduces ER expression and decreases sensitivity to hormonal agents in breast cancer cells. Our preliminary study has also shown that a hypoxic cytotoxin, tirapazamine, increases ER expression in breast cancer xenografts. Differential antitumor activity of tirapazamine on tumor cells under normoxic or hypoxic conditions may cause this phenomenon. These findings suggest that hypoxic cytotoxins may retard the development of endocrine resistance induced by hypoxia. Molecular mechanisms responsible for endocrine resistance in breast cancer are reviewed and possible therapeutic strategies against this resistance are discussed.

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Acknowledgments

This work was supported by Research Project Grants (15-501 and 16-501S) from Kawasaki Medical School and by a grant (14571166) from the Ministry of Education, Science, Sports and Culture of Japan.

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  1. Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan

    Junichi Kurebayashi

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Correspondence to Junichi Kurebayashi.

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This work was presented at the 20th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium, “New Concepts of Treatment Strategies for Hormone-Related Cancer”, 11–12 March 2005, Nagoya, Japan.

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Kurebayashi, J. Resistance to endocrine therapy in breast cancer. Cancer Chemother Pharmacol 56 (Suppl 1), 39–46 (2005). https://doi.org/10.1007/s00280-005-0099-z

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