| Stat5a plays a pivotal role in mammary gland development and has been implicated in breast cancer. PI3K pathways contribute through a plethora of functions to both normal physiology and tumorigenesis in many organs. In vitro studies in the hematopoietic system demonstrated an interaction between Stat5 and the p85 regulatory subunit of PI3K, as well as functional cooperation between these two critical survival pathways in promoting oncogenesis. The overall goal of my thesis was to explore the in vivo functional consequences of the interaction between Stat5a and Pik3r1 pathways on mammary gland development and tumorigenesis. A genetic approach employing two knockout mouse models, Stat5a and Pik3r1 (the gene which encodes all three p85alpha regulatory isoforms), was undertaken to test my hypothesis that loss of the main regulatory subunits of class IA P13Ks and associated activity would alter Stat5a signaling in the mammary gland.;In virgin hosts, Pik3r1-/- mammary transplants showed significantly impaired ductal development (reduced ductal growth and branching), similarly to Stat5a-/- phenotype. However, while it was reported that numerous terminal end buds are retained in Stat5a-/- transplants (indicative of incomplete differentiation), no terminal end buds were found in Pik3r1-/- abdominal mammary transplants.;During late pregnancy, Pik3r1-/- mammary transplants were able to terminally differentiate, as opposed to Stat5a-/- transplants which fail to differentiate. Importantly, there were no statistically significant changes in levels of activated Stat5 in Pik3r1-/- transplants when compared to the control group. Also, no statistically significant changes were detected in the WAP and β-casein milk protein expression, two markers of functional differentiation whose expression is reduced significantly in Stat5a-/- transplants. Finally, Cyclin D1 protein, but not mRNA expression was reduced considerably in Stat5a-/- mammary tissues, whereas no statistically significant difference was found in Pik3r1-/- transplants.;In the WAP-TAg mouse model of breast cancer, haploid deficiency of Stat5a gene delays cancer progression. In contrast, haploid deficiency of Pik3r1 locus did of alter mammary tumorigenesis in the same mouse model.;In summary, the main regulatory subunits of class IA PI3Ks and associated activity are not necessary for proper Stat5a activation and downstream signaling in the mammary gland. |
