p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response

Abstract

The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response.

Hypermethylation of the Gene Body in SRCIN1 Is Involved in Breast Cancer Cell Proliferation and Is a Potential Blood-Based Biomarker for Early Detection and a Poor Prognosis

“…Preliminary studies have suggested that SRCIN1 may act either as an oncogene or as a tumor suppressor. SRCIN1 might suppress β-catenin in the breast cancer stem cell niche, thereby promoting antitumor immune defense [58,59]. Reduced SRCIN1 expression led to decreased cell viability in the MCF-7, T47D and MDA-MB-231 breast cancer cell lines, as confirmed by more than three technical and biological replicates (Figure 5C-E).…”

p140Cap modulates the mevalonate pathway decreasing cell migration and enhancing drug sensitivity in breast cancer cells

“…In a subgroup analysis of the patients of the TGCA cohort, stratified for the different BC molecular subtypes (i.e. luminal, Her2+ and triple-negative-TNBC), we recently reported that, compared to luminal and Her2+ patients, TNBC patients showed significantly reduced expression levels of SRCIN1 transcript and p140Cap protein levels, indicating that BC with clinico-pathological features of aggressiveness, such as TNBCs, display comparatively lower level of the tumor suppressor p140Cap [ 31 ]. The present data indicating that p140Cap is a new player in the regulation of plasma membrane fluidity, may add a further layer of complexity to the stratification of TNBC, where the levels of p140Cap may be used as clinical biomarker for tumor aggressiveness.…”

“…In particular, we have found that p140Cap exerts a negative control on in vivo tumor growth and metastasis formation in Luminal A [ 25 ], Her2-amplified [ 27 ], and in triple-negative BC cell models [ 25 , 26 ]. Indeed, p140Cap is able to reduce cancer cells aggressiveness through specific molecular mechanisms, such as the down-regulation of Src kinase activity [ 25 ], and the Rac-Tiam1 axis [ 5 , 22 , 27 ], or by inhibiting the β-Catenin activity in cancer stem cells and modulating the immune tumor microenvironment [ 30 , 31 ]. We have previously described the interactome of p140Cap in BC, in which proteins belonging to the Metabolism category in the KEGG functional division, in general, are well-represented [ 32 ].…”

The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity

“…G-CSFAs underlined by their name, the main feature of MDSCs is immunosuppression. We recently described the ability of the adaptor protein p140Cap to counteract the mobilization and intratumor accumulation of polymorphonuclear myeloid-derived suppressive cells (PMN-MDSC), to prevent the establishment of a tumor conducive immune environment ( 56 ). (Salemme et al., 2023 in press).…”