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Molecular therapy of breast cancer: progress and future directions

Abstract

Breast cancer is a major cause of death in Western women, with a 10% lifetime risk of the disease. Most breast cancers are estrogen-dependent. Molecular therapies for breast cancer have developed rapidly in the past few decades and future treatment strategies are being investigated. The selective estrogen receptor (ER) modulator tamoxifen, which until now has served as a standard therapy, functions not only as an estrogen antagonist but also as an estrogen agonist in terms of bone maintenance. Aromatase inhibitors have performed well in international trials and have become a new standard therapy for estrogen-dependent breast cancer. The systematic study of estrogen activation pathways suggests that the enzymes steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 1, which both have pivotal roles in estrogen biosynthesis, are promising targets; the results of a phase I trial of steroid sulfatase inhibitors are encouraging. The activity of the human epidermal growth factor receptor (HER) pathway correlates negatively with that of the ER. HER2 is overexpressed in 22% of all breast cancers. In the decade since HER2 began being targeted, the monoclonal antibody trastuzumab has been used as well as pertuzumab and HER2 vaccines. Among the estrogen-independent breast cancers, the basal-like subtype has low survival, and therapeutic improvement is a priority. Crosstalk between ER and HER2 signaling pathways means that combinatory therapies may hold the key to enhancement of treatment responses. Other molecular therapies involving functional genomics and RNA interference studies also hold promise.

Key Points

  • Use of the selective estrogen receptor modulator tamoxifen and aromatase inhibitors constitute two important milestones in the treatment of estrogen-dependent breast cancer

  • Systematic study of estrogen activation pathways suggests that steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 1 are the next promising targets

  • Human epidermal growth factor receptor (HER) positive breast cancer can be treated with the monoclonal antibody trastuzumab, pertuzumab, HER2 vaccines or the protein kinase inhibitor lapatinib

  • RNA silencing and genomic study open new avenues for treatment

  • Combinatory therapies are beneficial because of the cross talk between estrogen receptor and HER2 signaling pathways

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Figure 1: Chemical structures of standard drugs for the treatment of estrogen-dependent breast cancers, and a steroid sulfatase inhibitor in the early stages of clinical development.
Figure 2: Enzymatic mechanisms involved in the formation and transformation of estrogens in human breast cancer.

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Acknowledgements

We acknowledge the financial support of the Canadian Institutes of Health Research (CIHR) to S.-X. Lin and D. Poirier, as well as the studentship from LSBV, IBCB (SIBS) with S.-X. Lin. The authors thank Muriel Kelly for careful editing of the manuscript.

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S.-X. Lin and J. Chen researched the data for the article. S.-X. Lin, M. Mazumdar, D. Poirier, C. Wang, A. Azzi and M. Zhou provided a substantial contribution to discussions of the content. S.-X. Lin and J. Chen wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Sheng-Xiang Lin.

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Lin, SX., Chen, J., Mazumdar, M. et al. Molecular therapy of breast cancer: progress and future directions. Nat Rev Endocrinol 6, 485–493 (2010). https://doi.org/10.1038/nrendo.2010.92

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