Cytoplasmic cyclin E mediates resistance to aromatase inhibitors in breast cancer

Iman Doostan, Cansu Karakas, Mehrnoosh Kohansal, Kwang Hui Low, Matthew J. Ellis, John A. Olson, Vera Jean Suman, Kelly K. Hunt, Stacy L. Moulder, Khandan Keyomarsi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E–mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E–positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E–mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.

Original languageEnglish (US)
Pages (from-to)7288-7300
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2017

Fingerprint

Cyclin E
Aromatase Inhibitors
Molecular Weight
Breast Neoplasms
letrozole
Hormones
Neoplasms
Cell Cycle
Therapeutics
Neoadjuvant Therapy
Aromatase
MCF-7 Cells
Cytostatic Agents
Tumor Burden
Heterografts
Research Design
Clinical Trials
Recurrence
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Doostan, I., Karakas, C., Kohansal, M., Low, K. H., Ellis, M. J., Olson, J. A., ... Keyomarsi, K. (2017). Cytoplasmic cyclin E mediates resistance to aromatase inhibitors in breast cancer. Clinical Cancer Research, 23(23), 7288-7300. https://doi.org/10.1158/1078-0432.CCR-17-1544

Cytoplasmic cyclin E mediates resistance to aromatase inhibitors in breast cancer. / Doostan, Iman; Karakas, Cansu; Kohansal, Mehrnoosh; Low, Kwang Hui; Ellis, Matthew J.; Olson, John A.; Suman, Vera Jean; Hunt, Kelly K.; Moulder, Stacy L.; Keyomarsi, Khandan.

In: Clinical Cancer Research, Vol. 23, No. 23, 01.12.2017, p. 7288-7300.

Research output: Contribution to journalArticle

Doostan, I, Karakas, C, Kohansal, M, Low, KH, Ellis, MJ, Olson, JA, Suman, VJ, Hunt, KK, Moulder, SL & Keyomarsi, K 2017, 'Cytoplasmic cyclin E mediates resistance to aromatase inhibitors in breast cancer', Clinical Cancer Research, vol. 23, no. 23, pp. 7288-7300. https://doi.org/10.1158/1078-0432.CCR-17-1544
Doostan I, Karakas C, Kohansal M, Low KH, Ellis MJ, Olson JA et al. Cytoplasmic cyclin E mediates resistance to aromatase inhibitors in breast cancer. Clinical Cancer Research. 2017 Dec 1;23(23):7288-7300. https://doi.org/10.1158/1078-0432.CCR-17-1544
Doostan, Iman ; Karakas, Cansu ; Kohansal, Mehrnoosh ; Low, Kwang Hui ; Ellis, Matthew J. ; Olson, John A. ; Suman, Vera Jean ; Hunt, Kelly K. ; Moulder, Stacy L. ; Keyomarsi, Khandan. / Cytoplasmic cyclin E mediates resistance to aromatase inhibitors in breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 23. pp. 7288-7300.
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abstract = "Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E–mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E–positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E–mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.",
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AU - Doostan, Iman

AU - Karakas, Cansu

AU - Kohansal, Mehrnoosh

AU - Low, Kwang Hui

AU - Ellis, Matthew J.

AU - Olson, John A.

AU - Suman, Vera Jean

AU - Hunt, Kelly K.

AU - Moulder, Stacy L.

AU - Keyomarsi, Khandan

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