microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer
Sharon Wang, Jeff C. Liu, YoungJun Ju, Giovanna Pellecchia, Veronique Voisin, Dong-Yu Wang, Rajwinder Leha l, Yaacov Ben-David, Gary D. Bader, Eldad Zacksenhaus
Sharon Wang, Jeff C. Liu, YoungJun Ju, Giovanna Pellecchia, Veronique Voisin, Dong-Yu Wang, Rajwinder Leha l, Yaacov Ben-David, Gary D. Bader, Eldad Zacksenhaus
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Research Article Oncology

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

Abstract

The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce nonmalignant 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 harbor 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 (miR-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, miR-145 deficiency significantly correlated with elevated RAS-pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/high RAS-pathway activity exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with RAS-pathway activation, either through miR-145 loss or other mechanisms, in basal-like breast cancer, and a need to identify and prioritize these tumors for aggressive therapy.

Authors

Sharon Wang, Jeff C. Liu, YoungJun Ju, Giovanna Pellecchia, Veronique Voisin, Dong-Yu Wang, Rajwinder Leha l, Yaacov Ben-David, Gary D. Bader, Eldad Zacksenhaus

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Figure 4

Low miR-145 expression in PTEN-deficient breast cancer leads to poor clinical outcome.

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Low miR-145 expression in PTEN-deficient breast cancer leads to poor cli...
(A) Microarray analysis of miR levels in poorly differentiated adenocarcinomas (PDAs) versus adenomyoepitheliomas (AMEs). miR-145 is downregulated by 7.4-fold in PDAs relative to AMEs. Both miR-143 and miR-145 are significantly downregulated in PDAs. PDA n = 8, AME n = 13. Circles represent individual data points. Bars represent mean ± SD. (B) Quantitative real-time PCR confirms miR-145 downregulation in tumorspheres derived from PDAs. *P = 0.03, Student’s t test. miR-143 n ≥ 3, miR-145 n ≥ 3. Circles represent individual data points. Whiskers represent minimum to maximum value. Box bounds represent 25th to 75th percentiles. Line within box represents the mean. No outlying values. (C) Analysis of miR-143 expression in human breast cancer (BC) database. Mir-143 levels are downregulated in all BC subtypes compared with normal-like breast tissue. ANOVA, Bonferroni: *P < 0.05, **P < 0.01, ***P < 0.0001. Basal n = 16, HER2 n = 19, luminal A n = 45, luminal B n = 16, normal-like n = 13. Whiskers represent minimum to maximum value. Box bounds represent 25th to 75th percentiles. Line within box represents the mean. No outlying values. (D) Analysis of miR-145 expression in human BC database. Aggressive basal-like and luminal B cancers show downregulated miR-145 expression. ANOVA, Bonferroni: *P < 0.05, **P < 0.01. Basal n = 15, HER2 n = 17, luminal A n = 41, luminal B n = 12, normal-like n = 10. Whiskers represent minimum to maximum value. Box bounds represent 25th to 75th percentiles. Line within box represents the mean. No outlying values. (E) Significant correlation between low PTEN and miR-145 gene expression, primarily in basal-like (0.33) as well as other BC subtypes. P < 0.01. (F) Percentage of tumors with low PTEN and low miR-145 expression, showing highest prevalence in basal-like BC relative to all other subtypes. Student’s t test, P < 0.0403. (G) Kaplan-Meier disease-free survival analysis showing patients with PTEN-low and miR-145–low have poorer prognosis than patients with PTEN-high and miR-145–low. Wilcoxon method, P = 0.0505. miR-145–low/PTEN-high n = 42; miR-145–low/PTEN-low n = 13; miR-145–high/PTEN-high n = 109; miR-145–high/PTEN-low n = 15.