Basal cells expressing p63 contain multipotent stem cells that can efficiently differentiate during postnatal prostate morphogenesis, adult prostate epithelial homeostasis and carcinogenesis. Our project aim is to investigate p63 expression by focusing on the rates of basal epithelial cell proliferation/differentiation in the ventral prostate after intrauterine undernutrition (IUN) associated with or without hormonal exposure in adult life. Briefly, 20 Sprague Dawley dams were distributed equally into two groups during gestation: control diet (NP; fed a normal diet containing 17% protein) and restricted protein diet (RP, fed a diet containing 6% protein). After birth, all animals were maintained on the control diet. Experiment 1: To analyze p63 expression during prostate development, NP and RP animals were euthanized at postnatal day (PND) 3, 10, 21 and 35. The ventral prostate (VP) was dissected, weighed and processed for IHC (Ki67, p63 and AR) and Western blot (WB) analysis (PCNA, p63 and AR). Experiment 2: To analyze p63 expression in adults after hormonal exposure, 14 week-old NP and RP animals were subjected to 17-beta estradiol+testosterone administration (subcutaneous implant) for 16 weeks. The animals were killed at 35 weeks old and the VP was excised, weighed and processed for IHC and WB analysis. RP treated animals showed lower body weight compared to NP control treated animals. Reductions of testosterone plasma levels as well as the absolute and relative values of VP weights from the RP animals compared to the NP animals were observed. Normal glandular architecture was observed in both groups at PND 3, 10, 21 and 35. There was a reduction of AR expression in VP from RP animals at all ages analyzed. However, the proliferation rate and p63+ cells were higher in the RP group indicating that the low androgenic stimulation induced by IUN promoted a delay in VP development. As a consequence, the proliferation/differentiation cell dynamic was impaired, leading to an increase in basal cell number and damaging their differentiation into secretory luminal cells. We observed in hormone exposed adults that prostatitis aggressiveness and prostatic intraepithelial neoplasia (PIN) incidence were higher in the RP compared to NP animals. These results were followed by a decrease in apoptosis index and increases in proliferation rate and p63+ cells. It is clear that IUN alters adult prostate response to androgen/estrogen exposure and interferes in adult prostate susceptibility to diseases. In conclusion, IUN-induced fetal programming impairs ventral prostate growth, maturation and homeostasis highlighting the importance of adequate nutritional status during embryonic/fetal development.
Note: This abstract was not presented at the meeting.
Citation Format: Jaqueline C. Rinaldi, Caroline N. Barquilha, Sergio AA Santos, Ana C. Camargo, Ketlin T. Colombelli, Sergio L. Felisbin, Luis A. Justulin. Analysis of p63 protein expression in rat ventral prostate submitted to intrauterine undernutrition associated to hormonal exposure in adult life. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 827. doi:10.1158/1538-7445.AM2015-827