Abstract
The estrogen receptor-alpha (ERα) is used as a predictive marker for anti-estrogen therapy in breast cancer patients. In addition to aromatase inhibitors, ERα 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 (ERβ), as a therapeutic target or prognostic marker in breast cancer is still elusive. Hitherto, it is not known if ERα+/ERβ+ breast cancers would benefit from a treatment strategy combining tamoxifen and fulvestrant or if fulvestrant exert any therapeutic effects in ERα-/ERβ+ breast cancer. Here, we report that fulvestrant up-regulated ERβ in ERα+/ERβ+ breast cancer and in triple negative ERβ+ breast cancers (ERα-/ERβ+). In ERα+/ERβ+ 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 ERα-/ERβ+ 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 ERβ. The role of ERβ was further confirmed in cells where ERβ was knocked-in or knocked-down. Inhibition of DNA methyltransferase (DNMT) increased the levels of ERβ 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 ERα+/ERβ+ breast cancer where fulvestrant synergizes with tamoxifen and ii) in triple negative/ERβ+ breast cancer patients, a subgroup of breast cancer patients with poor prognosis.
Highlights
Estrogen exposure is implicated in the development and progression of breast cancer and approximately two thirds of all breast cancers express estrogen receptor alpha (ERα) [1]
ERα-/ERβ+ breast cancers belong to the triple-negative breast cancer (TNBC) group, a subgroup of breast cancers characterized by the lack of expression of ERα, progesterone receptor, and human epidermal growth factor receptor-2 (HER-2) [23]
To test if tumor regression of ERα+/ERβ+ breast cancer could be enhanced by a combination treatment of fulvestrant and tamoxifen, MCF-7 breast cancer explants were established in nude mice
Summary
Estrogen exposure is implicated in the development and progression of breast cancer and approximately two thirds of all breast cancers express estrogen receptor alpha (ERα) [1]. The SERD fulvestrant, ICI 182,780, on the other hand, acts as a pure anti-estrogen by hindering receptor dimerization, increasing receptor turnover, and disrupting the nuclear localization of ERα [5, 6]. This is a marked contrast to the stable or even increased ERα expression caused by tamoxifen [5]. In the metastatic setting the FACT study, fulvestrant in combination with anastrozol, did not offer any advantage compared to anastrozol alone [9] In these trials ERα was determined and targeted. ERβ may be a potential target in TNBC but this has previously not been fully explored
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