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CoQ10 (Coenzyme Q10) is an essential fat-soluble metabolite that plays a key role in cellular metabolism. A less-known function of CoQ10 is whether it may act as a plasma membrane-stabilizing agent and whether this property can affect cancer development and progression. Here, we show that CoQ10 and its biosynthetic enzyme UBIAD1 play a critical role in plasmamembrane mechanical properties that are of interest for breast cancer (BC) progression and treatment. CoQ10 and UBIAD1 increase membrane fluidity leading to increased cell stiffness in BC. Furthermore, CoQ10 and UBIAD1 states impair ECM (extracellular matrix)-mediated oncogenic signaling and reduce ferroptosis resistance in BC settings. Analyses on human patients and mouse models reveal that UBIAD1 loss is associated with BC development and progression and UBIAD1 expression in BC limits CTCs (circulating tumor cells) survival and lung metastasis formation. Overall, this study reveals that CoQ10 and UBIAD1 can be further investigated to develop therapeutic interventions to treat BC patients with poor prognosis. The roles of CoQ10 and producing enzymes in cancer have not been well explored. Here, the authors identify that the CoQ10-biosynthetic enzyme UBIAD1 is a tumor suppressor in breast cancer. CoQ10 induced alterations in plasma membrane mechanical properties lead to increased cellular stiffness and impaired tumorigenic signaling, as well as enhanced sensitivity to ferroptosis. [ABSTRACT FROM AUTHOR]

Transformation of normal cells into tumor cells requires the accumulation of a series of genetic and epigenetic events (1,2), and it can be reversed under a variety of conditions (3-6). [...], Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer.

Author(s): Ivan N. Colaluca [1, 2]; Daniela Tosoni [1, 2]; Paolo Nuciforo [1]; Francesca Senic-Matuglia [1]; Viviana Galimberti [2]; Giuseppe Viale [2, 3]; Salvatore Pece (corresponding author) [1, 2, 3]; [...]

ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor. In this paper, we found that antibodies (Abs) targeting different epitopes on the ERBB2 extracellular domain foster the activation of ERBB2 homodimers, and surprisingly induce a unique cytostatic signaling cascade promoting an ERK-dependent ERBB2 Thr701 phosphorylation, leading to AKT de-phosphorylation, via PP2A Ser/Thr phosphatases. Furthermore, the immunophilin Cyclophilin A plays a crucial role in this pathway, acting as a negative modulator of AKT de-phosphorylation, possibly by competing with Ser/Thr phosphatases for binding to AKT. Altogether, our data show that Ab recognizing ERBB2 extracellular domain function as receptor agonists, promoting ERBB2 homodimer activation, leading to an anti-proliferative signaling. Thus, the ultimate outcome of ERBB2 activity might depend on the dimerization status: pro-oncogenic in the hetero-, and anti-oncogenic in the homo-dimeric form. [ABSTRACT FROM AUTHOR]

Approximately 20% of breast cancers display ERBB2 (HER2) gene amplification and/or protein overexpression. In cancer cells, ERBB2 can function both in the homodimeric and heterodimeric form. Moreover, it represents the preferred partner of other members of the ERBB receptor family. Strikingly, ERBB2-containing heterodimers are more oncogenic than other ERBB combinations, mostly by promoting cell proliferation via ERK activation and cell survival via the AKT pathway. AKT signalling plays a fundamental role in driving breast carcinogenesis and is downmodulated in response to the binding of the humanized therapeutic antibody Trastuzumab (TZ) to ERBB2. How ERBB2 differentially modulates AKT in ERBB2-overexpressing BrCa cells upon TZ treatment, remain unclear. Our findings show that TZ treatment of ERBB2- positive breast cancer cell lines triggers the homodimerization and the activation of ERBB2, leading to an previously unidentified signalling cascade causing an ERK-dependent AKT dephosphorylation, via PP2A Ser/Thr phosphatases. The immunophilin Cyclophilin A (CyPA) plays a key role in this pathway, as a negative modulator of AKT de-phosphorylation, by competing with PP2A phosphatases for binding to AKT. Upon TZ treatment ERK promotes CyPA redistribution to ERBB2, allowing the binding of PP2A to phospho-AKT. Finally, we report that CyPA silencing reverts TZ-resistant human ERBB2-positive breast cancer cell lines to a TZresponsive state. In conclusion, we show that in breast cancer cells TZ promotes ERBB2 activation, working as a "putative" ligand of the receptor, and that the outcome of the ERBB2 activity depends on the dimerization status: pro-oncogenic in the hetero- and anti-proliferative in the homodimeric form. [ABSTRACT FROM AUTHOR]

Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs. [ABSTRACT FROM AUTHOR]

Normal and tumor stem cells are present in rare quantities in tissues and this has historically represented a major hurdle to in-depth investigations of their biology. In the case of the mammary gland, the relative promiscuity of the immunophenotypical markers described in several studies for the isolation of human and mouse mammary stem cells limits their usefulness, in particular when highly purified mammary stem cell fractions are required for an in-depth molecular and functional characterization (Stingl et al. Nature 439:993-997, 2006; Shackleton et al. Nature 439:84-88, 2006; Liao et al. Cancer Res 67:8131-8138, 2007; Eirew et al. Nat Med 14:1384-1389, 2008; Raouf et al. Cell Stem Cell 3:109-118, 2008; Lim et al. Nat Med 15:907-913, 2009). In fact, most so-called stem cell markers are not selectively expressed by mammary stem cells, but are instead also expressed by terminally differentiated luminal and/or myoepithelial cells or by bipotent progenitors within the mammary gland (Stingl et al. Nature 439:993-997, 2006; Eirew et al. Nat Med 14:1384-1389, 2008; Raouf et al. Cell Stem Cell 3:109-118, 2008; Stingl et al. Differentiation 63:201-213, 1998; Jones et al. Cancer Res 64:3037-3045, 2004). Here, we describe a new methodology that does not require the use of immunophenotypical markers to obtain highly pure populations of mammary stem cells. This approach exploits two functional properties of mammary stem cells: (1) their quiescent or slowly proliferative phenotype, as compared to their progeny; and (2) their ability to survive and proliferate in anchorage-independent conditions, giving rise to clonal spheroids, commonly known as "mammospheres" (Dontu et al. Genes Dev 17:1253-1270, 2003; Pece et al. Cell 140:62-73, 2010; Cicalese et al. Cell 138:1083-1095, 2009). In the context of mammospheres, stem cells, which perform one or two rounds of division and then reenter quiescence, are identified based on their ability to retain a lipophilic fluorescent dye, PKH26, that is by contrast progressively lost by dilution in the actively proliferating progeny of precursors (Pece et al. Cell 140:62-73, 2010; Cicalese et al. Cell 138:1083-1095, 2009). Following mammosphere dissociation, the differential degree of PKH26 epifluorescence displayed by stem cells compared to precursor cells is exploited for their purification by FACS sorting. As a result, the scarcely represented PKH26-labeled mammary stem cells are purified to near homogeneity and can be used for further molecular and biological studies.