Truncated ASPP2 Drives Initiation and Progression of Invasive Lobular Carcinoma via Distinct Mechanisms

Abstract

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 (PP1) 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, YAP1 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. Statement of significanceTruncated 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 YAP1 activation enhances tumor progression.

The oncogenic roles and clinical implications of YAP/TAZ in breast cancer

“…Tao et al found that YAP expression was dramatically elevated in p53 loss-driven mammary tumours from luminal cells, indicating a potential cooperation between Yap overexpression and p53 -loss in BC development [ 44 ]. Besides, YAP activation was also found to be required for t-ASPP2-induced invasive lobular carcinoma (ILC) growth and progression [ 45 ]. Taken together, all these findings highlight the key roles of YAP/TAZ in both breast epithelial lineage commitment, and BC progression and metastasis.…”

Invasive lobular carcinoma of the breast: the increasing importance of this special subtype

“…Murine genetic screens using transposon mutagenesis facilitated the identification of truncating mutations in ASPP2 (Trp53bp2) as a novel oncogenic driver in ILC [118]. It has since been shown that this variant is involved in the initiation and progression of ILC growth, dependent on its cooperative interactions with the actin cytoskeleton, E-cadherin loss, and PI3K activation through PTEN loss [122].…”

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions

“…To identify novel ILC driver genes, an in vivo insertional mutagenesis screen yielded multiple candidates, several of which were subsequently used to generate novel GEMMs of ILC [128]. Two of these models, which combined mammary-specific loss of E-cadherin with overexpression of truncated variants of Mypt1 or Aspp2, showed that a reduction in actomyosin contractility is sufficient to drive the malignant transformation of E-cadherin deficient mammary epithelial cells [128,129]. The tumors typically displayed classic ILC features but were not tested for ER expression or dependency.…”

“…Interestingly, both models showed rapid tumor initiation but slow tumor growth, a common characteristic of ILCs. Additional loss of PTEN resulted in faster tumor initiation and larger tumors [129]. In vivo validation of a third hit from the insertional mutagenesis screen, TRPS1, showed that while TRPS1 expression is essential for the survival of mammary epithelial cells, combined loss of TRPS1 and E-cadherin expression resulted in accelerated tumor development [130].…”