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MicroRNA-143/145 loss induces Ras-signaling and cooperates with Pten-deficiency to promote basal-like breast cancer [gene expression]

ABSTRACT: The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce non-malignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse Pten in mammary epithelium are highly differentiated and lack transplantable tumor initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbour transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations and mutational landscape, as well as reduced expression of microRNA-143/145. Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable Pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR145-deficiency significantly correlated with elevated RAS pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/RAS pathway activation exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with miR-145 loss or high RAS-pathway activity in aggressive forms of breast cancer, and a need to identify and prioritize these tumors for aggressive therapy. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other models of mouse mammary tumors

ORGANISM(S): Mus musculus

PROVIDER: GSE99493 | GEO | 2017/06/02

SECONDARY ACCESSION(S): PRJNA388659

REPOSITORIES: GEO

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microRNA-143/145 loss induces Ras-signaling and cooperates with Pten-deficiency to promote basal-like breast cancer [CGH]

Project description:The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce non-malignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse Pten in mammary epithelium are highly differentiated and lack transplantable tumor initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbour transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations and mutational landscape, as well as reduced expression of microRNA-143/145. Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable Pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR145-deficiency significantly correlated with elevated RAS pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/RAS pathway activation exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with miR-145 loss or high RAS-pathway activity in aggressive forms of breast cancer, and a need to identify and prioritize these tumors for aggressive therapy. Array CGH data comparing 2 types of Pten-deficient tumors (well and poorly differentiated) with other modles of mouse mammary tumors

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Project description:microRNA-143/145 loss induces Ras-signaling and cooperates with Pten-deficiency to promote basal-like breast cancer [CGH]

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