RESUMEN
Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the immune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in the expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFß; p = 0.049), whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFß in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Factor de Transcripción GATA3/genética , Interferón gamma/genética , Yodo/administración & dosificación , Factor de Crecimiento Transformador beta1/genética , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Apoptosis/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Inmunidad/genética , Yodo/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , México , Persona de Mediana Edad , RNA-Seq , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Epidemiological studies on micronutrient consumption have reported protective associations in the incidence and/or progression of various cancer types. Supplementation with some of these micronutrients has been analyzed, showing chemoprotection, low toxicity, antiproliferation, and the ability to modify epigenetic signatures in various cancer models. This review investigates the reported effects of micronutrient intake or supplementation in breast cancer progression. A PubMed search was conducted with the keywords "micronutrients breast cancer progression", and the results were analyzed. The selected micronutrients were vitamins (C, D, and E), folic acid, metals (Cu, Fe, Se, and Zn), fatty acids, polyphenols, and iodine. The majority of in vitro models showed antiproliferative, cell-cycle arrest, and antimetastatic effects for almost all the micronutrients analyzed, but these effects do not reflect animal or human studies. Only one clinical trial with vitamin D and one pilot study with molecular iodine showed favorable overall survival and disease-free interval.
Asunto(s)
Neoplasias de la Mama/patología , Micronutrientes , Femenino , Humanos , Yodo/administración & dosificación , Oligoelementos/administración & dosificación , Vitamina D/administración & dosificaciónRESUMEN
This study analyzes an oral supplement of molecular iodine (I2), alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I2 (5 mg/day) or placebo (colored water) for 7-35 days before surgery. For the Advanced group, 30 patients received I2 or placebo, along with FEC/TE treatment. After surgery, all patients received FEC/TE + I2 for 170 days. I2 supplementation showed a significant attenuation of the side effects and an absence of tumor chemoresistance. The control, I2, FEC/TE, and FEC/TE + I2 groups exhibited response rates of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients treated with the I2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% versus 46%). I2-treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial to analyze chemotherapy + I2 treatment for advanced breast cancer.