ROLE OF p27Kip1 IN MAMMARY GLAND DEVELOPMENT AND TUMORIGENESIS IN Δ16HER2 MODEL

Breast Cancer is the most frequent cancer among women worldwide. The oncogene HER2 is amplified and overexpressed in about 15-20% of invasive BC and is associated with poor prognosis. A splice variant of the human HER2 gene, the Δ16HER2, displaying enhanced transforming activity, has been identified in BC patients. p27kip1 is a well-known cell cycle inhibitor whose expression is frequently downmodulated in tumors, including BC. However, its role in HER2 BC remains elusive and we thus decided to investigate the impact of p27 loss in Δ16HER2-driven breast cancer onset and progression. Δ16HER2p27KO mice shown a marked anticipation in tumor onset and significantly augmented tumor growth rate. Analysis of tumors indicates that the absence of p27 impinges both on number and volume of tumors, leading to the development of a lower number of pre-neoplastic and frank lesions that result increased in size. Δ16HER2 tumor-derived epithelial cells, either WT or p27KO, displayed increased growth rate when injected in p27KO recipient mice, thus indicating that p27 mainly plays a cell non-autonomous function in Δ16HER2-driven tumor growth. Mammary tissue analysis suggested the presence of a larger CD45+ leukocyte population in Δ16p27KO pre-neoplastic tissue. Examination of cytokines in mammary and serum samples disclosed the presence of several molecules involved in inflammatory response and immune cells maturation and recruitment. Studies on mammary gland structure in Δ16p27KO virgin female mice at pre-tumorigenic stage highlighted that mice p27KO display alterations of the mammary architecture, resembling a lactating phenotype. We found higher prolactin levels in Δ16p27KO mammary glands, leading to an aberrant activation of PRLR patwhway. Collectively, our data indicate that loss of p27 in Δ16HER2 model induces a profound alteration of mammary gland structure at early stage of transformation and an acceleration of the tumorigenic process, mainly via cell non-autonomous mechanism.