Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis
Authors: Deepa Subramanyam
Rekha V Kumar
Devaveena Dey
Annapoorni Rangarajan
Suruchi Mittal
Journal: Molecular Cancer (2009)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Notch signaling; breast cancer progression; expression analysis; Notch receptors; ligands
Affiliations: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560 012, Karnataka, India. 

Abstract:  Background: Recent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression. Results: We report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in approximately 75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis. Conclusions: High level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with the Ras/MAPK pathway in transformation offers combined inhibition of the two pathways as a new modality for breast cancer treatment. 

Retracted: No

PubPeer comments:
 Figs 2D,E.  (D) Overexpression of miR-144-3p decreased migration of PANC-1 cells detected by Transwell assay. (E) Overexpression of miR-144-3p decreased invasion of PANC-1 cells detected by Transwell assay . Figs 4D,E.  (D) Transwell assay indicated that the migration ability of PANC-1 cells was markedly attenuated by downregulation of FOSB. (E) Transwell assay indicated that siFOSB significantly decreased the invasion ability of PANC-1 cells .  Overlaps marked. Very similar smoky, smudgy exercises in fumage can be found in (e.g.) [Zhang et al (2017)] , or [Wang et al (2017)] . Plagiarising [a comment by Elisabeth Bik] : This paper belongs to a set of over 400 papers (as per February 2020) that share very similar Western blots with tadpole-like shaped bands, the same background pattern, and striking similarities in title structures, paper layout, bar graph design, and - in a subset - flow cytometry panels. Despite these similarities, these papers are authored by researchers from different departments and institutes, with almost no overlap in authors. The list of these papers is available here: https: docs.google.com spreadsheets d 1KXqTAyl4j-jVorFPMD2XRpr76LcIKJ0CVyIvRj0exYQ edit?usp=sharing A more detailed description of this set of papers, suspected to all be generated by a common source, a paper mill , can be found here: - https: forbetterscience.com 2020 01 24 the-full-service-paper-mill-and-its-chinese-customers (January 2020) - https: scienceintegritydigest.com 2020 02 21 the-tadpole-paper-mill (February 2020) The same paper mill has been described in these papers: - Jana Christopher - Systematic fabrication of scientific images revealed - FEBS Letters (2018) - https: febs.onlinelibrary.wiley.com doi full 10.1002 1873-3468.13201 - Jennifer A Byrne and Jana Christopher - Digital magic, or the dark arts of the 21st centuryu2014how can journals and peer reviewers detect manuscripts and publications from paper mills? - FEBS Letters (2020) - https: febs.onlinelibrary.wiley.com doi full 10.1002 1873-3468.13747 , 
 In the absence of a response from the authors, here are Figs 2C and 4C,  Overexpression of miR144-3p reduced cell colony formation and  Colony formation among siFOSB, siFOSB + anti-miR-144-3p, and their appropriate controls. Repeated modified panels are indicated.  ,