El objetivo de este trabajo es estudiar la influencia de distintos niveles de actividad pineal sobre la inducción y el crecimiento de tumores mamarios hormonodependientes. El aumento de la actividad pineal obtenido por asociación de ceguera con bulbectomía olfatoria, subnutrición o exposición a bajas temperaturas produjo: a) descenso de la incidencia tumoral y aumento del tiempo de latencia de aparición de los tumores; b) descenso en el número de tumores y en la superficie tumoral; c) descenso de la concentración de receptores estrogénicos tumorales y de los niveles circulantes de estradiol; d) inhibición del crecimiento de tumores previamente inducidos. Los efectos antitumorales de la actividad pineal pueden ser explicados por acciones antiestrogénicas directas a nivel del tumor, dado que manteniendo constantes los niveles de estradiol, mediante ovariectomía y administración de estrógenos, la hiperactividad pineal indujo una marcada regresión tumoral acompañada de un descenso de la concentración de receptores estrogénicos en el tejido tumoral. / The aim of this work was to study the influence of different levels of pineal activity on the genesis and growth of hormonodependent mammary tumors. The enhancement of pineal actions by experimental manipulations like blindness+anosmia, blindness+underfeeding or blindness+cold exposure, in relation with pinealectomized animals, produced the following effects: a) a decrease in tumor incidence and an increase in the latency in the appearance of tumors; b) a decrease in tumor number and tumor size; c) a decrease in tumor estrogen receptor concentration and serum estradiol; d) an inhibition of tumors previously induced.. A pineal-induced decrease in serum estradiol levels as well as in the concentration of estrogenic receptors in tumoral tissue could be in part responsible for these pineal antitumoral actions.

Both p130Cas and PKN3 are important regulators of cellular signaling deregulation of which leads to malignant behavior of cancer cells. Recently we have found that SH3 domain of p130Cas mediates interaction with proline rich region of PKN3 suggesting their possible cooperation in regulation of these processes. In this work we have focused on the phosphorylation of p130Cas by PKN3 and identified serine 498 (S498) within the serine rich domain of p130Cas to be phosphorylated by PKN3 in vitro. Given that S498 is localized within the 14-3-3 binding motif and its phosphorylation is required for interaction of p130Cas with 14-3-3 proteins, we propose potential existence of novel PKN3/p130Cas/14-3-3 signaling axis. In the second part of the work we have studied this pathway in response to antiestrogen treatment in estrogen receptor positive breast cancer cell line MCF7. Although we have shown inactivation of PKN3 occurs as an early response to tamoxifen treatment, we do not rule out its possible role in further promotion of resistance to antiestrogens. Furthermore, understanding the signaling triggered by interaction of PKN3 with p130Cas and its possible downstream effects on promoting malignant growth of cancer cells would help in finding novel therapeutic targets.

<p>Sintetisana su nova jedinjenja, 16- i 17-supstituisani&nbsp;16,17-sekoestratrienski derivati i D-homoestranski&nbsp;derivati, polazeći od 3-benziloksi-17-hidroksi-16,17-sekoestra-1,3,5(10)-trien-16-nitrila. Ispitana je&nbsp;estrogena i antiestrogena aktivnost u eksperimentima <em>in&nbsp;vivo</em>, antiaromatazna aktivnost <em>in vitro</em>, antioksidantna&nbsp;aktivnost DPPH &nbsp;i TBA testom, kao i antiproliferativna&nbsp;aktivnost prema ćelijskim linijama MCF-7 ATCC,&nbsp;MDA-MB-231, HT-29 i MRC-5 novosintetisanih&nbsp;jedinjenja.</p> / <p>Some new compounds, 16- and 17-substituted 16,17-secoestratriene derivatives, as&nbsp; well as D-homoestratriene derivatives, were synthesized, starting from 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5 (10)-triene-16-nitrile. The newly synthesized compounds were tested for their <em>in vivo&nbsp;</em>estrogenic and antiestrogenic activity,&nbsp; <em>in vitro&nbsp;</em>antiaromatase activity, antioxidative activity by DPPH and TBA tests, as well as antiproliferative activity against MCF-7 ATCC, MDA-MB-231, HT-29 i MRC-5 cell lines.</p>