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Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ER alpha positive breast cancer by up-regulation of ER beta
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 35, p. 56876-56888Article in journal (Refereed) Published
Abstract [en]

The estrogen receptor-alpha (ER alpha) is used as a predictive marker for antiestrogen therapy in breast cancer patients. In addition to aromatase inhibitors, ER alpha can be targeted at the receptor level using the receptor modulator tamoxifen or by the pure anti-estrogen fulvestrant. The role of the second ER, ER-beta (ER beta), as a therapeutic target or prognostic marker in breast cancer is still elusive. Hitherto, it is not known if ER alpha+/ER beta+ breast cancers would benefit from a treatment strategy combining tamoxifen and fulvestrant or if fulvestrant exert any therapeutic effects in ER alpha-/ER beta+ breast cancer. Here, we report that fulvestrant up-regulated ER beta in ER alpha+/ER beta+ breast cancer and in triple negative ER beta+ breast cancers (ER alpha-/ER beta+). In ER alpha+/ER beta+ breast cancer, a combination therapy of tamoxifen and fulvestrant significantly reduced tumor growth compared to either treatment alone both in vivo and in vitro. In ER alpha-/ER beta+ breast cancer fulvestrant had potent effects on cancer growth, in vivo as well as in vitro, and this effect was dependent on intrinsically expressed levels of ER beta. The role of ER beta was further confirmed in cells where ER beta was knocked-in or knocked-down. Inhibition of DNA methyltransferase (DNMT) increased the levels of ER beta and fulvestrant exerted similar potency on DNMT activity as the DNMT inhibitor decitabine. We conclude that fulvestrant may have therapeutic potential in additional groups of breast cancer patients; i) in ER alpha+/ER beta+ breast cancer where fulvestrant synergizes with tamoxifen and ii) in triple negative/ER beta+ breast cancer patients, a subgroup of breast cancer patients with poor prognosis.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC , 2016. Vol. 7, no 35, p. 56876-56888
Keywords [en]
mammary cancer; sex steroids; steroid receptors; proliferation; DNA methyltransferase
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-132866DOI: 10.18632/oncotarget.10871ISI: 000386911600075PubMedID: 27486755OAI: oai:DiVA.org:liu-132866DiVA, id: diva2:1052357
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council [2013-2457]; LiU-Cancer; Research Funds of Linkoping University Hospital

Available from: 2016-12-06 Created: 2016-11-30 Last updated: 2018-03-19

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Abrahamsson, AnnelieDabrosin, Charlotta
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