El objetivo de la presente tesis doctoral era estudiar los mecanismos de invasión, el papel de diferentes factores de crecimiento, el estudio de la vía PI3K/Akt/mTOR y evaluar la respuesta al tratamiento en el cáncer de mama. Previamente habíamos estudiado las mutaciones del PIK3CA en una serie de pacientes con carcinoma de mama en las que encontramos asociación de mutaciones de PIK3CA con el subgrupo de los pacientes con tumores HER2 +. Además la presencia de mutaciones de PIK3CA se asoció a peor supervivencia. La introducción de trastuzumab ha cambiado la historia natural de las pacientes con tumores HER2+ por lo tanto decidimos incorporar al estudio pacientes que habían recibido este fármaco. En este artículo encontramos al menos una alteración de la vía PI3K en un cuarto de los tumores, además demostramos las complejas interacciones entre EGFR, IGFR1R i la vía PTEN/PI3K/Akt/Bad y mTOR, que están relacionados con mecanismos de resistencia a trastuzumab. Para completar el estudio decidimos analizar otro receptor de membrana, como LRP-1 o “low density lipoprotein receptor-related protein 1”. Este es un miembro de la familia de receptores de colesterol que presenta homología parcial con EGFR. En nuestro estudio detectamos la expresión de LRP1 en el 14% de los tumores, además esta se correlacionaba con alto grado nuclear, alto índice mitótico y Ki67 elevado. Además la expresión de LRP1 se asoció a tumores de tipo triple negativo que sobreexpresaban EGFR y HER2+. El síndrome hipermetabólico (obesidad, intolerancia a la glucosa, bajo HDL, hipertrigliceridemia e hipertensión) se ha asociado a tumores de tipo triple negativo. En nuestra serie las pacientes con tumores de tipo triple negativo y HER2+ mostraron mayores niveles de colesterol. Se ha relacionado la sobreexpresión de LRP1 con hipercolesterolemia en estudios “in vivo”. En nuestra serie encontramos mayores cifras de colesterol en las pacientes que sobreexpresaban LRP1, aunque los resultados no fueron estadísticamente significativos. En conclusión hemos corroborado la importancia que tienen los receptores de membrana en el cáncer de mama. También que el estado de activación de los diferentes efectores de la vía del PI3K/akt/mTOR pueden influir en la resistencia a fármacos como Trastuzumab. También hemos demostrado que otros receptores de membrana como LRP1 (con homología parcial con EGFR) están implicados en el carcinoma de mama y se relacionan con la invasión. Además es muy interesante la relación de este último con los niveles de colesterol y el síndrome hipermetabólico. / The objective of the present thesis was to study the mechanisms of invasion, the role of different growth factor receptors, the impact of the PI3K/Akt/Mtor pathway and the response to treatment in breast carcinoma. In a previous study we found association of PIK3CA mutations with HER2 postive breast carcinomas, moreover PIK3CA mutations were associated with poor prognosis. The introduction of trastuzumab in the treatment of HER2 positive breast carcinoma has dramatically changed his natural history, for this reason we decided to select patients which has received trastuzumab in her treatment. We found in about one-forth of HER2 tumours at least one molecular alteration in the PI3K pathway and/or its upstream or downstream effectors. Our data support the complex interactions between EGFR, IGF1R, and the PTEN/PI3K/Akt/Bad and mTOR signalling pathway, which in turn are potentially related with the mechanisms of trastuzumab response. To complete our study we selected another membrane receptor such as low density lipoprotein receptor-related protein 1 or LRP-1. This receptor is a member of the cholesterol receptors and has partial homology with EGFR. In our study we found LRP-1 expression in 14% of the tumours and was related with high nuclear grade, high mitotic index and high proliferation index (Ki 67). Also, LRP-1 expression was present in HER2 positive and triple negative tumours with EGFR expression. The hypermetabolic syndrome (obesity, glucose intolerance, low HDL, hypertriglyceridemia and hypertension) has been associated with triple negative tumors. In our series patients with triple negative and HER2 positive tumors had higher cholesterol levels, although this association was not statistically significant. In conclusion we have confirmed the role of membrane receptors in breast carcinomas. Also activation of their downstream effectors such as the PI3K/akt/mTOR pathway can be related to trastuzumab resistance. We have demonstrated that other membrane receptors such as LRP-1 (with partial homology with EGFR) are related to breast carcinoma and their mechanisms of invasion. Moreover, the relationship between LRP-1 cholesterol levels and the hypermetabolic syndrome are very interesting, but further studies are needed.

Endometrial cancer is one of the most significant gynaecological malignancies that affect women from New Zealand and the rest of the world. One of the critical stages in the development of a tumour is the onset of hypoxia. The malignancy responds by having raised levels of Hypoxia Inducible Factor (HIF) that in turn induces increased production of Vascular Endothelial Growth Factor (VEGF). VEGF is a potent angiogenic factor that will mediate vascular supply of nutrients and oxygen to the developing tumour. The aim of this study was to investigate whether two compounds found in extracts of plant materials, Resveratrol (Resveratrol) and Epigallocatechin gallate (EGCG), altered the levels of VEGF in the supernatant of cultured endometrial cancer cells. Resveratrol is a phytoalexin that is found in many foods, such as grapes, nuts and berries, as well as in high concentrations in some red wines. 100 µM of resveratrol was added to cell cultures for 24 hours. VEGF levels in the supernatant were then analysed using ELISA. Resveratrol was found to have significant inhibitory effects in both primary endometrial cancer cell cultures and immortalised endometrial cancer cell cultures. Resveratrol was also shown to reverse the increase in VEGF caused by the hypoxia mimic cobalt chloride (CoCl₂). Epigallocatechin gallate (EGCG) is an antioxidant catechin extracted from green tea. The effect of EGCG was analysed using the same method as for resveratrol. 100 µM of EGCG was also shown to have a significant inhibitory effect on the level of VEGF in the supernatant of cultured endometrial cancer cells, as well as reducing the effect of CoCl₂. These results suggest that selected food compounds, resveratrol and EGCG, can reduce VEGF levels by inhibiting HIF. Further investigation This may have anti-tumour effects in women with endometrial cancer.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 132-174) Also available in print.

Thesis (M.S.)--Missouri University of Science and Technology, 2009. / Vita. The entire thesis text is included in file. Title from title screen of thesis/dissertation PDF file (viewed April 13, 2009) Includes bibliographical references (p. 46).

Thesis (M. Phil.)--University of Hong Kong, 2008. / Also available online.

Thesis (M. Phil.)--University of Hong Kong, 2008.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 132-174) Also available online.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [61]-68).