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Upregulation of estrogen receptor alpha (ERα) expression in transgenic mice expressing human CYP4Z1

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

CYP4Z1 is a human cytochrome P450 enzyme involved in breast cancer progression and prognosis, but its functional role in these processes is not understood. In order to gain more insight into CYP4Z1’s properties it was recombinantly expressed in a host animal that does not have an endogenous homologue.

Methods

We generated a transgenic mouse model that specifically expresses human CYP4Z1 in breast tissue under the control of the whey acidic protein promoter. Complementary experiments were done using cell lines derived from human breast cell.

Results

Induction of CYP4Z1 expression led to reduction of body weight, activity, and birth rates. Histological analysis revealed no evidence for tumor formation. However, a strong increase in estrogen receptor alpha was observed by immunohistochemistry; weaker but significantly increased immunoreactivity was also detected for collagen I and fibronectin. Overexpression of CYP4Z1 in the human breast cancer cell line MCF7 also led to increased ERα expression. Moreover, increased expression of both CYP4Z1 and ERα was observed in MCF-10A normal breast cells upon cocultivation with MCF-7 cells (with or without overexpression of CYP4Z1).

Conclusion

These data suggest that CYP4Z1 facilitates breast cancer development by induction of ERα expression via an as yet undefined mechanism.

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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AI:

Aromatase inhibitor

BC:

Breast cancer

CYP:

Human cytochrome P450 enzyme

Cyp:

Mouse cytochrome P450 enzyme

E2:

Estradiol

ER:

Estrogen receptor

ROS:

Reactive oxygen species

SERD:

Selective estrogen receptor degrader

SERM:

Selective estrogen receptor modulator

WAP:

Whey acidic protein

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Acknowledgements

The authors thank Lu Xinran and Li Futian of the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences, Tianjin, for technical support in rearing and monitoring of the animals used in this study. We also thank Wu Che-lin of Beijing Maid Conner Biotechnology for technical assistance in the pathology work of this study.

Funding

No funding was received.

Author information

Authors and Affiliations

  1. School of Pharmaceutical Science and Technology (SPST), Tianjin University, Tianjin, China

    Christopher Khayeka-Wandabwa, Jie Zhao, Janak L. Pathak, Huiyuan Wu & Matthias Bureik

  2. Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China

    Janak L. Pathak

Authors
  1. Christopher Khayeka-Wandabwa
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  2. Jie Zhao
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  3. Janak L. Pathak
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  4. Huiyuan Wu
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  5. Matthias Bureik
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Contributions

Conceptualization: CKW, JLP, HW, and MB; experimental work: CKW and JZ; formal analysis and visualization: CKW and MB; writing: CKW, JLP, HW, and MB. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Matthias Bureik.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures for handling of animals were approved by the institutional animal research ethical committee (protocol number IRM20180503).

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Khayeka-Wandabwa, C., Zhao, J., Pathak, J.L. et al. Upregulation of estrogen receptor alpha (ERα) expression in transgenic mice expressing human CYP4Z1. Breast Cancer Res Treat 191, 319–326 (2022). https://doi.org/10.1007/s10549-021-06435-w

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  • DOI: https://doi.org/10.1007/s10549-021-06435-w

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