Abstract
BackgroundZoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro.Materials and methodsUsing assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol.ResultsIn the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively).ConclusionWe have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.
Highlights
More than 50% of breast cancer patients present with early-stage endocrine-sensitive disease
We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid (ZA) in hormone sensitive, but not in hormone insensitive breast cancer cell lines
Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal
Summary
More than 50% of breast cancer patients present with early-stage endocrine-sensitive disease. In this subgroup, breast cancer outcomes have improved significantly over time partly because of the increasing availability of highly efficacious adjuvant therapies. Aromatase inhibitors and Tamoxifen have been shown to increase DFS in premenopausal breast cancer patients but these therapies are burdened with bone loss [1]. The only two phase III trials that considered cancer-specific primary endpoints and compared adjuvant therapy with and without ZA (ABCSG-12 and AZURE) independently suggested that adjuvant ZA can improve breast cancer outcome in patients with low levels of estrogen and after induced or natural menopause [13,14,15]. We have investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro
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