Abstract
IntroductionHER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects.MethodsThe effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed.ResultsIn HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells.ConclusionsCombining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.
Highlights
HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively
In the present article we examine the effects of various retinoids, trastuzumab, tamoxifen, or combinations of these drugs on proliferation, cell cycle, differentiation, and apoptosis in BT474 and SKBR3 cells
Analysis of interactions between all-trans retinoic acid (atRA), trastuzumab, and tamoxifen on cell proliferation ER-positive/HER2-overexpressing BT474 cells were treated with atRA, trastuzumab or tamoxifen at a range of doses (0.2 to 10 μM for atRA and tamoxifen, and 0.2 to 10 μg/ml for trastuzumab) and with various combinations of the three drugs at fixed dose ratios
Summary
HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. HER2 and estrogen receptor (ER) play critical roles in the clinical care of breast cancer patients as both prognostic factors and therapeutic targets. 9-cis-RA and 13-cis-RA bind both RARs and RXRs. N-(4-hydroxyphenyl) retinamide (4-HPR, fenretinide) is a synthetic analog of atRA [23,24,25] that has shown anti-tumor activity, but may have differing mechanisms of action. The receptor dimers bind to retinoic acid response elements or retinoid X response elements in the promoter sequences of target genes, and they modulate gene transcription [23,24,25]
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