TGFβ Induces “BRCAness” and Sensitivity to PARP Inhibition in Breast Cancer by Regulating DNA-Repair Genes

Abstract

Transforming growth factor β (TGFβ) proteins are multitasking cytokines, whose high levels at tumor sites generally correlate with poor prognosis in human cancer patients. Previously it was reported that TGFβ downregulates the expression of ataxia telangiectasia mutated (ATM) and mutS homolog 2 (MSH2) in breast cancer (BC) cells through a 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 miR-181 family. Correlations between the expression levels of TGFβ1 and the miR-181/BRCA1 axis were observed in primary breast tumor specimens. By downregulating BRCA1, ATM, and MSH2, TGFβ orchestrates DNA damage response (DDR) in certain BC 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 BCs 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 sporadic breast cancer patients for PARP interventions, which have exhibited beneficial effects in patients carrying BRCA mutations.

TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia

“…SMAD3 also counteracts BRCA1-dependent repair of DNA double-strand breaks in human breast epithelial cells (Dubrovska et al, 2005). In addition, TGF-β pathway induces HR defects in breast cancer cells by regulating BRCA1, ATM, and MSH2 DNA repair genes (Liu et al, 2014). Moreover, TGF-β pathway activation promotes genomic instability by downregulating RAD51 protein expression in lung epithelial cells (Kanamoto et al, 2002).…”

Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas

“…[74] STAG2 contributes to the cohesion complex and has been proposed as a prognostic biomarker for bladder and pancreatic cancer. [75–77] MSH2 appears to play a complex role in breast cancer biology in which expression of the gene can be associated with tumor suppression [78, 79] or oncogenesis [80–82] depending on the context. One possible explanation is that MSH2 may be downregulated as a breast cancer becomes invasive, but then MSH2 expression becomes associated with breast cancer progression as the continued proliferation of tumor cells requires increased DNA mismatch repair.…”

Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

“…For example, increased TGF β signaling caused hypersensitivity to PARP inhibition in BT474 but not in MCF7 cells [145]. Meanwhile, knockdown of ATM by siRNA significantly increased sphere-forming efficiency (SFE) in BT474 and MDA361 but not in MCF7 cells.…”