Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer

Rangel, Maria Cristina; Bertolette, Daniel C.; Castro, Nadia P.; Klauzinska, Malgorzata; Cuttitta, Frank; Salomon, David

doi:10.1007/s10549-016-3746-7

Cited by 82 publications

(66 citation statements)

References 123 publications

(188 reference statements)

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“…A subset of highly tumorigenic cells in basal breast cancers have been shown to reactivate developmental signaling pathways such as those dependent on Notch, Wnt, or Sox2 (34, 69–71). Pharmacologic inhibition of Wnt (with the Porcupine inhibitor IWP2) or Notch (with the γ-secretase inhibitor compound E) reduced the self-renewal potential of colonies similarly to APT1 knockdown or APT1 and CDC42 double knockdown (fig.…”

Section: Resultsmentioning

confidence: 99%

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

2018

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Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which in turns drives migration and metastasis. Here, we report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1. Using point mutations, we show specific palmitoylated residues on Numb are required for asymmetric localization. By live-cell imaging, we show that reciprocal interactions between APT1 and the Rho-family GTPase CDC42 promote the asymmetric localization of Numb and β-catenin to the plasma membrane. This in turn restricts Notch- and Wnt-responsive transcriptional activity to one daughter cell. Moreover, we show altering APT1 expression changes the transcriptional signatures of MDA-MB-231 triple receptor–negative breast cancer cells similarly to changes in Notch and β-catenin–mediated Wnt signaling. We also show that loss of APT1 depletes a specific subpopulation of tumorigenic cells in colony formation assays. Together, our findings demonstrate that APT1-mediated depalmitoylation is a major mechanism of asymmetric cell division maintaining Notch and Wnt-associated protein dynamics, gene expression, and cellular functions.

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Section: Resultsmentioning

confidence: 99%

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

2018

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“…They also hold promise for the treatment of disorders caused by imbalanced stem cell differentiation such as cancer and osteoporosis [2, 3]. Stem cell signaling programs are complex and vary across tissues and developmental processes.…”

Section: Introductionmentioning

confidence: 99%

High-content image informatics of the structural nuclear protein NuMA parses trajectories for stem/progenitor cell lineages and oncogenic transformation

Vega

Liu

Arvind

et al. 2017

Experimental Cell Research

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Stem and progenitor cells that exhibit significant regenerative potential and critical roles in cancer initiation and progression remain difficult to characterize. Cell fates are determined by reciprocal signaling between the cell microenvironment and the nucleus; hence parameters derived from nuclear remodeling are ideal candidates for stem/progenitor cell characterization. Here we applied high-content, single cell analysis of nuclear shape and organization to examine stem and progenitor cells destined to distinct differentiation endpoints, yet undistinguishable by conventional methods. Nuclear descriptors defined through image informatics classified mesenchymal stem cells poised to either adipogenic or osteogenic differentiation, and oligodendrocyte precursors isolated from different regions of the brain and destined to distinct astrocyte subtypes. Nuclear descriptors also revealed early changes in stem cells after chemical oncogenesis, allowing the identification of a class of cancer-mitigating biomaterials. To capture the metrology of nuclear changes, we developed a simple and quantitative “imaging-derived” parsing index, which reflects the dynamic evolution of the high-dimensional space of nuclear organizational features. A comparative analysis of parsing outcomes via either nuclear shape or textural metrics of the nuclear structural protein NuMA indicates the nuclear shape alone is a weak phenotypic predictor. In contrast, variations in the NuMA organization parsed emergent cell phenotypes and discerned emergent stages of stem cell transformation, supporting a prognosticating role for this protein in the outcomes of nuclear functions.

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“…A variety of human malignancies, including breast cancers, brain tumors colon cancers, prostate cancers, and melanomas are thought to be organized in a hierarchy, whereby a relatively minor population of tumor initiating cells (TIC) or cancer stem cells (CSCs) is responsible for tumor growth and the vast majority of remaining cells is non-tumorigenic [68–70]. Treatment resistance for cancer can be either de novo – because of traits that tumor cells possess before treatment – or acquired – because of properties that tumor cells gain in response to treatment.…”

Section: Characterization Of Tumor-initiating Cells For Bc Using Mmtvmentioning

confidence: 99%

Clinical applications of mouse models for breast cancer engaging HER2/neu

Fry

Taneja

Inoue

2016

Integr Cancer Sci Therap.

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Human c-ErbB2 (HER2) has long been used as a marker of breast cancer (BC) for sub-categorization for the prediction of prognosis, and determination of therapeutic strategies. HER2 overexpressing BCs are more invasive/metastatic; but patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors, at least at early stages. To date, numerous mouse models that faithfully reproduce HER2(+) BCs have been created in mice. We recently reviewed different mouse models of BC overexpressing wild type or mutant neu driven by MMTV, neu, or doxycycline-inducible promoters. These mice have been used to demonstrate the histopathology, oncogenic signaling pathways initiated by aberrant overexpression of HER2 in the mammary epithelium, and interaction between oncogenes and tumor suppressor genes at molecular levels. In this review, we focus on their clinical applications. They can be used to test the efficacy of HER(2) inhibitors before starting clinical trials, characterize the tumor-initiating cells that could be the cause of relapse after therapy as well as to analyze the molecular mechanisms of therapeutic resistance targeting HER2. MMTV-human ErbB2 (HER2) mouse models have recently been established since the monoclonal antibody to HER2 (trastuzumab; Herceptin®) does not recognize the rat neu protein. It has been reported that early intervention with HER2 monoclonal antibody would be beneficial for preventing mammary carcinogenesis. MDA-7/IL-24 as well as naturally-occurring chemicals have also been tested using MMTV-neu models. Recent studies have shown that MMTV-neu models are useful to develop vaccines to HER2 for immunotherapy. The mouse models employing HER2/neu will be essential for future antibody or drug screenings to overcome resistance to trastuzumab or HER(2)-specific tyrosine kinase inhibitors.

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Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer

Cited by 82 publications

References 123 publications

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

High-content image informatics of the structural nuclear protein NuMA parses trajectories for stem/progenitor cell lineages and oncogenic transformation

Clinical applications of mouse models for breast cancer engaging HER2/neu

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