| First Author | Schipper K | Year | 2020 |
| Journal | Cancer Res | Volume | 80 |
| Issue | 7 | Pages | 1486-1497 |
| PubMed ID | 32060147 | Mgi Jnum | J:287289 |
| Mgi Id | MGI:6404365 | Doi | 10.1158/0008-5472.CAN-19-3607 |
| Citation | Schipper K, et al. (2020) Truncated ASPP2 Drives Initiation and Progression of Invasive Lobular Carcinoma via Distinct Mechanisms. Cancer Res 80(7):1486-1497 |
| abstractText | Invasive lobular carcinoma (ILC) accounts for 8%-14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell-cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin-deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2-induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2-induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression. SIGNIFICANCE: Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression. |
