The voltage gated Ca2+-channel Cav3.2 and therapeutic responses in breast cancer

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Abstract

Background

Understanding the cause of therapeutic resistance and identifying new biomarkers in breast cancer to predict therapeutic responses will help optimise patient care. Calcium (Ca ²⁺)-signalling is important in a variety of processes associated with tumour progression, including breast cancer cell migration and proliferation. Ca ²⁺-signalling is also linked to the acquisition of multidrug resistance. This study aimed to assess the expression level of proteins involved in Ca ²⁺-signalling in an in vitro model of trastuzumab-resistance and to assess the ability of identified targets to reverse resistance and/or act as potential biomarkers for prognosis or therapy outcome.

Methods

Expression levels of a panel of Ca ²⁺-pumps, channels and channel regulators were assessed using RT-qPCR in resistant and sensitive age-matched SKBR3 breast cancer cells, established through continuous culture in the absence or presence of trastuzumab. The role of Ca _v3.2 in the acquisition of trastuzumab-resistance was assessed through pharmacological inhibition and induced overexpression. Levels of Ca _v3.2 were assessed in a panel of non-malignant and malignant breast cell lines using RT-qPCR and in patient samples representing different molecular subtypes (PAM50 cohort). Patient survival was also assessed in samples stratified by Ca _v3.2 expression (METABRIC and KM-Plotter cohort).

Results

Increased mRNA of Ca _v3.2 was a feature of both acquired and intrinsic trastuzumab-resistant SKBR3 cells. However, pharmacological inhibition of Ca _v3.2 did not restore trastuzumab-sensitivity nor did Ca _v3.2 overexpression induce the expression of markers associated with resistance, suggesting that Ca _v3.2 is not a driver of trastuzumab-resistance. Ca _v3.2 levels were significantly higher in luminal A, luminal B and HER2-enriched subtypes compared to the basal subtype. High levels of Ca _v3.2 were associated with poor outcome in patients with oestrogen receptor positive (ER+) breast cancers, whereas Ca _v3.2 levels were correlated positively with patient survival after chemotherapy in patients with HER2-positive breast cancers.

Conclusion

Our study identified elevated levels of Ca _v3.2 in trastuzumab-resistant SKBR3 cell lines. Although not a regulator of trastuzumab-resistance in HER2-positive breast cancer cells, Ca _v3.2 may be a potential differential biomarker for survival and treatment response in specific breast cancer subtypes. These studies add to the complex and diverse role of Ca ²⁺-signalling in breast cancer progression and treatment.

Electronic supplementary material

The online version of this article (doi:10.1186/s12935-016-0299-0) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Elena Pera: epera@me.com

Elke Kaemmerer: e.kaemmerer@uq.edu.au

Michael J. G. Milevskiy: michael.milevskiy@uqconnect.edu.au

Kunsala T. D. S. Yapa: k.yapa@uq.edu.au

Jake S. O’Donnell: jake.odonnell@uq.edu.au

Melissa A. Brown: melissa.brown@uq.edu.au

Fiona Simpson: f.simpson@uq.edu.au

Amelia A. Peters: a.peters1@uq.edu.au

Sarah J. Roberts-Thomson: sarahrt@uq.edu.au

Gregory R. Monteith: gregm@uq.edu.au

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 31 March 2016

Publication date PMC-release: 31 March 2016

Publication date Collection: 2016

Volume: 16

Electronic Location Identifier: 24

Affiliations

[ ]The School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall St, Woolloongabba, Brisbane, QLD Australia

[ ]Mater Research Institute, The University of Queensland, Brisbane, QLD Australia

[ ]Translational Research Institute, Brisbane, QLD Australia

[ ]The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD Australia

[ ]Diamantina Institute, The University of Queensland, Brisbane, QLD Australia

Article

Publisher ID: 299

DOI: 10.1186/s12935-016-0299-0

PMC ID: 4815142

PubMed ID: 27034617

SO-VID: 21b2fc73-3b2d-4929-ad3b-87add3ba41f8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 February 2016

Date accepted : 22 March 2016

Funding

Funded by: NHMRC

Award ID: 1079672

Award Recipient : Gregory R. Monteith

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer,trastuzumab-resistance,calcium-signalling,cav3.2 (cacna1h),therapeutic response,biomarker

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer, trastuzumab-resistance, calcium-signalling, cav3.2 (cacna1h), therapeutic response, biomarker