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)... Show moreInvasive 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. Show less
Klarenbeek, S.; Doornebal, C.W.; Kas, S.M.; Bonzanni, N.; Bhin, J.; Braumuller, T.M.; ... ; Jonkers, J. 2020
Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3... Show moreEffective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1(Flox/Flox);Trp53(Flox/Flox) (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1(-/-) mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naive immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system. Show less
