Abstract A19: Stathmin plays a role in both normal and transformed mammary gland
Authors: Segatto Ilenia , Berton Stefania , D'Andrea Sara , Baldassarre Gustavo , Belletti Barbara 
Published: May 2016

Normal mammary gland is a highly dynamic organ and displays complex tissue architecture, precise breast epithelial cell hierarchy and lineage plasticity regulation. These features are thought to underlie the high degree of both inter- and intra-tumor heterogeneity of breast cancers (BC).

We have recently made the observation that stathmin knock-out (STMKO) female mice do not breast feed their first litter. Stathmin (also called Oncoprotein 18, OP18) is a microtubule-destabilizing protein. It is overexpressed in many human malignancies, including breast cancer, especially in advanced/metastatic disease. The phenotype that we observed suggested that complete development of lactating mammary gland was not properly and/or timely achieved in the absence of stathmin. To evaluate if this was the case, we analyzed mammary glands from WT and STMKO mice at prepuberal stage, at puberty, at day 13.5 of pregnancy and one day post-partum. Whole mount observation of mammary glands indicated that stathmin loss greatly impacted on the development of the mature gland, which displayed lower number of branches and defective alveolar buds. Most evident defects were displayed in the architecture of one day post-partum glands. Our molecular analyses showed that especially the polarity and the proliferation processes were affected by the absence of stathmin in the breast tissue.

Loss of polarity and deregulated proliferation are profoundly linked to epithelial tumorigenesis. We thus tested whether loss of stathmin had an impact on BC onset and/or progression, using a mouse model of HER2+ BC. Among the different BC subtypes, HER2+ tumors represent ~20% of invasive BC and display particularly aggressive phenotypes and poor prognosis. A splice variant of the human HER2 gene, called Delta16 HER2 (d16HER2), displaying enhanced transforming activity and associated with worse patients' survival, has been identified.

We intercrossed STMKO with d16HER2 transgenic mice and analyzed tumor onset, growth and progression in the different backgrounds. Our analysis showed that STMKO profoundly impacted on both tumor initiation and proliferation. The effect of stathmin on proliferation seemed to be mainly cell-autonomous, as observable by injecting BC cells extracted from d16HER2-STMKO, in either WT or STMKO recipient mice.

Thus, our results suggest that stathmin may play multiple roles in mammary epithelial cells. By regulating mammary epithelial cell polarity, it may be determinant in the definition of differentiation hierarchy, in cellular transformation and, eventually, tumor initiation. By regulating proliferation, it can affect tumor growth and burden. The unbalanced regulation of these critical processes certainly represents fertile ground for tumor initiation and may conceivably contribute to the great degree of tumor heterogeneity observed in breast cancer.

Citation Format: Ilenia Segatto, Stefania Berton, Sara D'Andrea, Gustavo Baldassarre, Barbara Belletti. Stathmin plays a role in both normal and transformed mammary gland. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A19.