Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences

Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.

PEAK3 pseudokinase represents a pro-migratory and -invasive signalling scaffold

The PEAK family of pseudokinases comprises PEAK1 and PEAK2 as well as the recently-identified PEAK3. PEAK1/2 play fundamental roles in regulating tyrosine kinase signal output and oncogenesis, while PEAK3 remains poorly-characterized. Here, we demonstrate that PEAK3 undergoes homotypic association as well as heterotypic interaction with PEAK1/2. PEAK3 also recruits ASAP1/2, Cbl and PYK2 and the adaptors Grb2 and CrkII, with binding dependent on PEAK3 dimerization. PEAK3 tyrosine phosphorylation on Y24 is also dependent on dimerization as well as Src family kinase activity, and interestingly, is decreased via PTPN12 in response to EGF treatment. Y24 phosphorylation is required for binding of Grb2 and ASAP1. Overexpression of PEAK3 in MDA-MB-231 breast cancer cells enhanced cell elongation and cell motility, while knockdown of endogenous PEAK3 decreased cell migration. In addition, overexpression of PEAK3 in PEAK1/2 compound knock-out MCF-10A breast epithelial cells enhanced acinar growth and invasion in 3D culture, with the latter phenotype dependent on PEAK3 tyrosine phosphorylation and binding of Grb2 and ASAP1. These findings characterize PEAK3 as an integral member of the PEAK family with scaffolding roles that promote cell proliferation, migration and invasion.

A direct heterotypic interaction between the DIX domains of Dishevelled and Axin mediates signaling to β-catenin

The Wnt–β-catenin signaling pathway regulates embryonic development and tissue homeostasis throughout the animal kingdom. Signaling through this pathway crucially depends on the opposing activities of two cytoplasmic multiprotein complexes: the Axin destruction complex, which destabilizes the downstream effector β-catenin, and the Dishevelled signalosome, which inactivates the Axin complex and thus enables β-catenin to accumulate and operate a transcriptional switch in the nucleus. These complexes are assembled by dynamic head-to-tail polymerization of the DIX domains of Axin or Dishevelled, respectively, which increases their avidity for signaling effectors. Axin also binds to Dishevelled through its DIX domain. Here, we report the crystal structure of the heterodimeric complex between the two DIX domains of Axin and Dishevelled. This heterotypic interface resembles the interfaces observed in the individual homopolymers, albeit exhibiting a slight rearrangement of electrostatic interactions and hydrogen bonds, consistent with the heterotypic interaction being favored over the homotypic Axin DIX interaction. Last, cell-based signaling assays showed that heterologous polymerizing domains functionally substituted for the DIX domain of Dishevelled provided that these Dishevelled chimeras retained a DIX head or tail surface capable of binding to Axin. These findings indicate that the interaction between Dishevelled and Axin through their DIX domains is crucial for signaling to β-catenin.