Inhibition of formyl peptide receptor 1 reduces the efficacy of anticancer chemotherapy against carcinogen-induced breast cancer

Abstract

The loss-of-function mutation of formyl peptide receptor 1 (FPR1) has a negative impact on the progression-free and overall survival of breast cancer patients treated with anthracycline-based adjuvant chemotherapy. This effect may be attributed to the fact that chemotherapy-induced antitumor immunity requires FPR1 and that such anticancer immune responses are responsible for the long-term effects of chemotherapy. Here, we investigated the possible contribution of FPR1 to the efficacy of a combination of mitoxantrone (MTX) and cyclophosphamide (CTX) for the treatment of hormone-induced breast cancer. Breast cancer induced by a combination of medroxyprogesterone acetate (MPA) and 7,12-Dimethylbenz[a]anthracene (DMBA) could be successfully treated with MTX plus CTX in thus far that tumor growth was retarded and overall survival was extended (as compared to vehicle-only treated controls). However, the therapeutic efficacy of the combination therapy was completely abolished when FPR1 receptors were blocked by means of cyclosporin H (CsH). Future genetic studies on neoadjuvant chemotherapy-treated breast cancers are warranted to validate these findings at the clinical level.

Keywords: Annexin A1; FPR1; chemotherapy; immunosurveillance; mammary carcinoma.

Figure 1.

Characteristics of the breast cancer model used in this study. Breast cancers were induced in young (7-weeks-old) female BALB/c mice by implantation of medroxyprogesterone acetate (MPA)-releasing pellets followed by gavage with the DNA damaging agent 7,12-Dimethylbenz[a]anthracene (DMBA) for the following 6 weeks. The overall scheme of the experiment is shown in (A). Note that the interval between the last DMBA injection and the manifestation of palpable breast cancer lesions is rather variable. This interval is demonstrated for each mouse that was subsequently randomized for assignment to different treatment groups, as shown in (B). PBS, phosphate buffered saline; CsH, cyclosporine H; CTX, cyclophosphamide; MTX, mitoxantrone.

Figure 2.

Effects of cyclosporin H on the efficacy of anticancer chemotherapy in a mouse model of breast cancers. (A) Immunocompetent BALB/c wild type (WT) mice bearing palpable hormone-induced mammary cancers received i.p. 5.17 mg/kg mitoxantrone (MTX) and 50 mg/kg cyclophosphamide (CTX) together with 30 mg/kg cyclosporin H (CsH) or an equivalent volume of phosphate buffered saline (PBS) and tumor growth was routinely assessed. Mice were treated when the tumor surface reached 25–35 mm² (day 0) and tumor growth was routinely assessed starting from the apparition of each tumor. Results from one representative experiment out of two independent ones involving at least four mice/group and yielding similar results are illustrated. Data are represented as means ± SEM over time. **p < 0.01, ***p < 0.001 (Wald test), as compared to PBS-treated tumors; ^###p < 0.05 (Wald test), as compared to MTX + CTX + CsH-treated tumors. Kaplan–Meier survival curves are shown in (B). n.s., non-significant, ***p < 0.001 (Log-Rank), as compared to PBS-treated tumors; ^##p < 0.01 (Log-Rank), as compared to MTX + CTX+ CsH-treated tumors.