TGFβ induces "BRCAness" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes.

Abstract

UNLABELLED:

Transforming growth factor beta (TGFβ) proteins are multitasking cytokines, in which high levels at tumor sites generally correlate with poor prognosis in human patients with cancer. Previously, it was reported that TGFβ downregulates the expression of ataxia telangiectasia-mutated (ATM) and mutS homolog 2 (MSH2) in breast cancer cells through an miRNA-mediated mechanism. In this study, expression of a panel of DNA-repair genes was examined, identifying breast cancer 1, early onset (BRCA1) as a target downregulated by TGFβ through the miR181 family. Correlations between the expression levels of TGFβ1 and the miR181/BRCA1 axis were observed in primary breast tumor specimens. By downregulating BRCA1, ATM, and MSH2, TGFβ orchestrates DNA damage response in certain breast cancer cells to induce a "BRCAness" phenotype, including impaired DNA-repair efficiency and synthetic lethality to the inhibition of poly (ADP-ribose) polymerase (PARP). Xenograft tumors with active TGFβ signaling exhibited resistance to the DNA-damaging agent doxorubicin but increased sensitivity to the PARP inhibitor ABT-888. Combination of doxorubicin with ABT-888 significantly improved the treatment efficacy in TGFβ-active tumors. Thus, TGFβ can induce "BRCAness" in certain breast cancers carrying wild-type BRCA genes and enhance the responsiveness to PARP inhibition, and the molecular mechanism behind this is characterized.

IMPLICATIONS:

These findings enable better selection of patients with sporadic breast cancer for PARP interventions, which have exhibited beneficial effects in patients carrying BRCA mutations.

• Authors: Liang Liu, Weiying Zhou, Chun-Ting Cheng, Xiubao Ren, George Somlo, Miranda Y Fong, Andrew R Chin, Hui Li, Yang Yu, Yang Xu, Sean Timothy Francis O'Connor, Timothy R O'Connor, David K Ann, Jeremy M Stark, Shizhen Emily Wang
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 12 Issue 11 Pg. 1597-609 (Nov 2014) ISSN: 1557-3125 [Electronic] United States
• PMID: 25103497 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• BRCA1 Protein
• MIrn181 microRNA, human
• MicroRNAs
• Poly(ADP-ribose) Polymerase Inhibitors
• Transforming Growth Factor beta
• Doxorubicin
• Poly(ADP-ribose) Polymerases
• Ataxia Telangiectasia Mutated Proteins
• MSH2 protein, human
• MutS Homolog 2 Protein

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• BRCA1 Protein (metabolism)
• Breast Neoplasms (genetics, pathology)
• Cell Line, Tumor
• DNA Repair (drug effects, genetics)
• Disease Progression
• Down-Regulation (drug effects, genetics)
• Doxorubicin (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Genomic Instability (drug effects)
• Humans
• Mice
• MicroRNAs
• MutS Homolog 2 Protein (metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Transforming Growth Factor beta (pharmacology)
• Triple Negative Breast Neoplasms (genetics, pathology)