Breast Cancer Research and Treatment

, Volume 173, Issue 2, pp 275–288 | Cite as

Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy

  • Fouzia Guestini
  • Katsuhiko Ono
  • Minoru Miyashita
  • Takanori Ishida
  • Noriaki Ohuchi
  • Saki Nakagawa
  • Hisashi Hirakawa
  • Kentaro Tamaki
  • Yasuyo Ohi
  • Yoshiaki Rai
  • Yasuaki Sagara
  • Hironobu Sasano
  • Keely May McNamaraEmail author
Preclinical study



Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms.


We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIα (TopoIIα), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC.


The status of vimentin and increasing labeling index (LI) of TopoIIα and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIα, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients.


KI67, TopoIIα, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC.


Triple-negative breast cancer Neoadjuvant chemotherapy Mechanistic markers Drug resistance Residual disease Outcomes 



Multidrug resistance 1 encoded by the gene ABCB1


Multidrug resistance protein 1 encoded by the gene ABCC1


Breast cancer resistance protein encoded by the gene ABCG2


B-cell lymphoma 2


Confidence interval


Complete response


Disease-free survival


Labeling index


Neoadjuvant chemotherapy


Odd ratio


Overall survival


Tumor protein 53


Pathologic complete response


Progressive disease


Partial response


Phosphatase and tensin homolog


Residual disease


Stable disease


Triple-negative breast cancer


Tumor, node, metastasis


Topoisomerase IIα



The author Fouzia Guestini work was supported by the Japanese Government Ministry of Education, Culture, Sports, Science, and Technology (MEXT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementary material

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Fouzia Guestini
    • 1
  • Katsuhiko Ono
    • 1
  • Minoru Miyashita
    • 1
  • Takanori Ishida
    • 1
  • Noriaki Ohuchi
    • 1
  • Saki Nakagawa
    • 1
  • Hisashi Hirakawa
    • 2
  • Kentaro Tamaki
    • 3
  • Yasuyo Ohi
    • 4
  • Yoshiaki Rai
    • 4
  • Yasuaki Sagara
    • 4
  • Hironobu Sasano
    • 1
  • Keely May McNamara
    • 1
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  1. 1.Tohoku UniversitySendaiJapan
  2. 2.Tohoku Kousai HospitalSendaiJapan
  3. 3.Nahanishi ClinicOkinawaJapan
  4. 4.Sagara HospitalKagoshimaJapan

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