PI3K signaling and adherens junctions in invasive lobular breast cancer

Klarenbeek, S. (2021)

Doctoral Thesis

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. Hallmarks of ILC include disruption of adherens junctions and hyperactivation of phosphoinositide 3-kinase (PI3K)-mTOR signaling. The tumor suppressor PTEN regulates PI3K signaling. We present a preclinical mouse model of ILC metastasis, based on inactivation of the adherens junction protein E-cadherin and the tumor suppressor p53 and surgical excision of primary tumors. In this model, pharmacological mTOR inhibition blocks growth of primary tumors as well as metastatic disease, and this response is partially dependent on the adaptive immune system. Loss of E-cadherin mouse mammary epithelium leads to apoptosis, and PTEN activation alone results in squamous metaplastic mammary tumors, but a combination of these events leads to ILC formation, indicating a causal role of PI3K signaling together with E-cadherin loss in ILC. Combined somatic loss of the adherens junction molecule p120 and p53 in the mouse mammary gland leads to metaplastic mammary tumors, and loss of p120 in breast cancer cell lines promotes anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Combined inactivation of E-cadherin, p120 and p53 induces basal-like tumors, with an epithelial-to- mesenchymal-transition (EMT) phenotype, and no ILC formation.

• Breast cancer
• Invasive lobular carcinoma (ILC)
• Mouse model
• PI3K
• mTOR
• Adherens junction
• E-cadherin
• p120

• All authors: Klarenbeek, S.
• Supervisor: Jonkers, J.
• Co-supervisor: Visser, K.E. de; Derksen, P.W.B.
• Committee: Irth, H.; Bouwstra, J.A.; Ossendorp, F.A.; Wesseling, J.; Danen, E.H.J.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
• Date: 2021-04-15
• ISBN (print): 9789464191585