MGMT Inhibition in ER Positive Breast Cancer Leads to CDC2, TOP2a, AUR, CDC20, KIFf20a, Cyclin A2, Cyclin B2, Cyclin D1, Erα and Survivin Inhibition and Enhances Response to Temozolomide

Authors

• George Bobustuc, Advocate Aurora Health
• Amin Kassam, Aurora Neurosciences Innovation Institute
• Richard Rovin, Aurora Neurosciences Innovation Institute
• Sheila Jeudy, Florida Hospital
• Joshua S. Smith, Florida Hospital
• Beth Isley, Florida Hospital
• Maharaj Singh, Marquette UniversityFollow
• Nathan David Sassoon, Texas Tech University Health Sciences Center
• Kalkunte S. Srivenugopal, Texas Tech University Health Sciences Center
• Santhi Konduri, Advocate Aurora Health

Document Type

Article

Publication Date

7-2018

Publisher

Impact Journals

Source Publication

Oncotarget

Source ISSN

1949-2553

Abstract

The DNA damage repair enzyme, O⁶-methylguanine DNA methyltransferase (MGMT) is overexpressed in breast cancer, correlating directly with estrogen receptor (ER) expression and function. In ER negative breast cancer the MGMT promoter is frequently methylated. In ER positive breast cancer MGMT is upregulated and modulates ER function. Here, we evaluate MGMT’s role in control of other clinically relevant targets involved in cell cycle regulation during breast cancer oncogenesis. We show that O⁶-benzylguanine (BG), an MGMT inhibitor decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, cyclin B2, A2, D1, ERα and survivin and induces c-PARP and p21 and sensitizes ER positive breast cancer to temozolomide (TMZ). Further, siRNA inhibition of MGMT inhibits CDC2, TOP2A, AURKB, KIF20A, Cyclin B2, A2 and survivin and induces p21. Combination of BG+TMZ decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, Cyclin A2, B2, D1, ERα and survivin. Temozolomide alone inhibits MGMT expression in a dose and time dependent manner and increases p21 and cytochrome c. Temozolomide inhibits transcription of TOP2A, AURKB, KIF20A and does not have any effect on CDC2 and CDC20 and induces p21. BG+/-TMZ inhibits breast cancer growth. In our orthotopic ER positive breast cancer xenografts, BG+/-TMZ decreases ki-67, CDC2, CDC20, TOP2A, AURKB and induces p21 expression. In the same model, BG+TMZ combination inhibits breast tumor growth in vivo compared to single agent (TMZ or BG) or control. Our results show that MGMT inhibition is relevant for inhibition of multiple downstream targets involved in tumorigenesis. We also show that MGMT inhibition increases ER positive breast cancer sensitivity to alkylator based chemotherapy.

Comments

Published version. Oncotarget, Vol. 9, No. 51 (2018): 29727-29742. DOI. © 2018 The Authors. Used with permission.

Maharaj Singh was affiliated with Aurora Research Institute and Aurora Neurosciences Innovation Institute at the time of publication.

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.

Recommended Citation

Bobustuc, George; Kassam, Amin; Rovin, Richard; Jeudy, Sheila; Smith, Joshua S.; Isley, Beth; Singh, Maharaj; Sassoon, Nathan David; Srivenugopal, Kalkunte S.; and Konduri, Santhi, "MGMT Inhibition in ER Positive Breast Cancer Leads to CDC2, TOP2a, AUR, CDC20, KIFf20a, Cyclin A2, Cyclin B2, Cyclin D1, Erα and Survivin Inhibition and Enhances Response to Temozolomide" (2018). College of Nursing Faculty Research and Publications. 1198.
https://epublications.marquette.edu/nursing_fac/1198