Supplemental Figures S1-S8 from Trastuzumab-Resistant HER2+ Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition

Wielgos, Monica E.; Zhang, Zhuo; Rajbhandari, Rajani; Cooper, Tiffiny S.; Zeng, Ling; Forero, Andres; Esteva, Francisco J.; Osborne, C. Kent; Schiff, Rachel; LoBuglio, Albert F.; Nozell, Susan E.; Yang, Eddy S.

doi:10.1158/1535-7163.22505161.v1

Supplemental Figures S1-S8 from Trastuzumab-Resistant HER2<sup>+</sup> Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition

https://doi.org/10.1158/1535-7163.22505161

journal contribution

posted on 2023-04-03, 15:06 authored by Monica E. Wielgos, Zhuo Zhang, Rajani Rajbhandari, Tiffiny S. Cooper, Ling Zeng, Andres Forero, Francisco J. Esteva, C. Kent Osborne, Rachel Schiff, Albert F. LoBuglio, Susan E. Nozell, Eddy S. Yang

<p>SFigure1: HER2+ breast cancer cells are sensitive to nirparib SFigure2: HER2+ breast cancer microtumors are sensitive to ABT-888 SFigure3: (A) ABT-888 reduces PAR levels in HER2+ xenograft models. (B) ABT-888 did not cause weight loss in mice SFigure4: Two different PARP-1 siRNAs decrease cell proliferation in HER2+ trastuzumab resistant breast cancer cells. SFigure5: Cell cycle distribution is not affected by PARPi in HER2+ trastuzumab resistant cell lines. SFigure6: IKK protein levels were decreased after treatment with Sigma-Aldrich''s PARP-1 siRNA. SFigure7: PARP-1 and IL-8 gene expression levels after PARP-1 knockdown or inhibition in HER2+ parental and trastuzumab resistant breast cancer cell lines. SFigure8: BRCA2 gene and protein expression levels in BT-474 trastuzumab resistant breast cancer cell lines after PARP-1 knockdown.</p>

Funding

American Association for Cancer Research

Genentech Career Development

Susan G. Komen

Breast Cancer Research Foundation

Breast SPORE

UAB

History

Related Materials

1.
DOI - Is supplement to Trastuzumab-Resistant HER2+ Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition

ARTICLE ABSTRACT

HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ breast cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR)–deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2+ trastuzumab-resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival in vitro and tumor growth in vivo of HER2+ TR breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-κB–regulated genes. In particular, silencing PARP-1 inhibited NF-κB activity and reduced p65 binding at the IL8 promoter, which resulted in a decrease in IL8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2+ breast cancer cells and support the testing of PARPi in patients with HER2+ breast cancer resistant to trastuzumab. Mol Cancer Ther; 17(5); 921–30. ©2018 AACR.