Plasma membrane expression of G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 (GPR30) is associated with worse outcome in metachronous contralateral breast cancer

Tutzauer, Julia; Sjöström, Martin; Bendahl, Pär Ola; Rydén, Lisa; Fernö, Mårten; Fredrik Leeb-Lundberg, L. M.; Alkner, Sara

Plasma membrane expression of G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 (GPR30) is associated with worse outcome in metachronous contralateral breast cancer

Mark

Tutzauer, Julia ^LU

; Sjöström, Martin ^LU ; Bendahl, Pär Ola ^LU ; Rydén, Lisa ^LU

; Fernö, Mårten ^LU ; Fredrik Leeb-Lundberg, L. M. ^LU and Alkner, Sara ^LU (2020) In PLoS ONE 15(4).

Abstract: Background G protein-coupled estrogen receptor (GPER), or G protein-coupled receptor 30 (GPR30), is reported to mediate non-genomic estrogen signaling. GPR30 associates with breast cancer (BC) outcome and may contribute to tamoxifen resistance. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance. Methods Total GPR30 expression (GPR30_TOT) and plasma membrane-localized GPR30 expression (GPR30_PM) were analyzed by immunohistochemistry in primary (BC1; n_BC1 = 559) and contralateral BC (BC2; n_BC2 = 595), and in lymph node metastases (LGL; n_LGL1 = 213; n_LGL2 = 196). Death from BC... (More); Background G protein-coupled estrogen receptor (GPER), or G protein-coupled receptor 30 (GPR30), is reported to mediate non-genomic estrogen signaling. GPR30 associates with breast cancer (BC) outcome and may contribute to tamoxifen resistance. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance. Methods Total GPR30 expression (GPR30_TOT) and plasma membrane-localized GPR30 expression (GPR30_PM) were analyzed by immunohistochemistry in primary (BC1; n_BC1 = 559) and contralateral BC (BC2; n_BC2 = 595), and in lymph node metastases (LGL; n_LGL1 = 213; n_LGL2 = 196). Death from BC (BCD), including BC death or death after documented distant metastasis, was used as primary end-point. Results GPR30_PM in BC2 and LGL2 were associated with increased risk of BCD (HR_BC2 = 1.7, p = 0.03; HR_LGL2 = 2.0; p = 0.02). In BC1 and BC2, GPR30_PM associated with estrogen receptor (ER)-negativity (p_BC1<0.0001; p_BC2<0.0001) and progesterone receptor (PR)-negativity (p_BC1 = 0.0007; p_BC2<0.0001). The highest GPR30_TOT and GPR30_PM were observed in triple-negative BC. GPR30_PM associated with high Ki67 staining in BC1 (p<0.0001) and BC2 (p<0.0001). GPR30_TOT in BC2 did not associate with tamoxifen treatment for BC1. However, BC2 that were diagnosed during tamoxifen treatment were more likely to express GPR30_PM than BC2 diagnosed after treatment completion (p = 0.01). Furthermore, a trend was observed that patients with GPR30_PM in an ER-positive BC2 had greater benefit from tamoxifen treatment. Conclusion PM-localized GPR30 staining is associated with increased risk of BC death when expressed in BC2 and LGL2. Additionally, PM-localized GPR30 correlates with prognostic markers of worse outcome, such as high Ki67 and a triple-negative subtype. Therefore, PM-localized GPR30 may be an interesting new target for therapeutic exploitation. We found no clear evidence that total GPR30 expression is affected by tamoxifen exposure during development of metachronous CBC, or that GPR30 contributes to tamoxifen resistance.
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Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/8f63163a-a515-4d06-83a1-9356dc7c64fa

author

Tutzauer, Julia ^LU

; Sjöström, Martin ^LU ; Bendahl, Pär Ola ^LU ; Rydén, Lisa ^LU

; Fernö, Mårten ^LU ; Fredrik Leeb-Lundberg, L. M. ^LU and Alkner, Sara ^LU

organization

publishing date

2020

type

Contribution to journal

publication status

published

subject

Cancer and Oncology

in

PLoS ONE

volume

15

issue

4

article number

e0231786

publisher

Public Library of Science (PLoS)

external identifiers

pmid:32302351
scopus:85083489846

ISSN

1932-6203

DOI

10.1371/journal.pone.0231786

language

English

LU publication?

yes

id

8f63163a-a515-4d06-83a1-9356dc7c64fa

date added to LUP

2020-05-07 12:11:17

date last changed

2024-10-17 02:59:13

@article{8f63163a-a515-4d06-83a1-9356dc7c64fa,
  abstract     = {{<p>Background G protein-coupled estrogen receptor (GPER), or G protein-coupled receptor 30 (GPR30), is reported to mediate non-genomic estrogen signaling. GPR30 associates with breast cancer (BC) outcome and may contribute to tamoxifen resistance. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance. Methods Total GPR30 expression (GPR30<sub>TOT</sub>) and plasma membrane-localized GPR30 expression (GPR30<sub>PM</sub>) were analyzed by immunohistochemistry in primary (BC1; n<sub>BC1</sub> = 559) and contralateral BC (BC2; n<sub>BC2</sub> = 595), and in lymph node metastases (LGL; n<sub>LGL1</sub> = 213; n<sub>LGL2</sub> = 196). Death from BC (BCD), including BC death or death after documented distant metastasis, was used as primary end-point. Results GPR30<sub>PM</sub> in BC2 and LGL2 were associated with increased risk of BCD (HR<sub>BC2</sub> = 1.7, p = 0.03; HR<sub>LGL2</sub> = 2.0; p = 0.02). In BC1 and BC2, GPR30<sub>PM</sub> associated with estrogen receptor (ER)-negativity (p<sub>BC1</sub>&lt;0.0001; p<sub>BC2</sub>&lt;0.0001) and progesterone receptor (PR)-negativity (p<sub>BC1</sub> = 0.0007; p<sub>BC2</sub>&lt;0.0001). The highest GPR30<sub>TOT</sub> and GPR30<sub>PM</sub> were observed in triple-negative BC. GPR30<sub>PM</sub> associated with high Ki67 staining in BC1 (p&lt;0.0001) and BC2 (p&lt;0.0001). GPR30<sub>TOT</sub> in BC2 did not associate with tamoxifen treatment for BC1. However, BC2 that were diagnosed during tamoxifen treatment were more likely to express GPR30<sub>PM</sub> than BC2 diagnosed after treatment completion (p = 0.01). Furthermore, a trend was observed that patients with GPR30<sub>PM</sub> in an ER-positive BC2 had greater benefit from tamoxifen treatment. Conclusion PM-localized GPR30 staining is associated with increased risk of BC death when expressed in BC2 and LGL2. Additionally, PM-localized GPR30 correlates with prognostic markers of worse outcome, such as high Ki67 and a triple-negative subtype. Therefore, PM-localized GPR30 may be an interesting new target for therapeutic exploitation. We found no clear evidence that total GPR30 expression is affected by tamoxifen exposure during development of metachronous CBC, or that GPR30 contributes to tamoxifen resistance.</p>}},
  author       = {{Tutzauer, Julia and Sjöström, Martin and Bendahl, Pär Ola and Rydén, Lisa and Fernö, Mårten and Fredrik Leeb-Lundberg, L. M. and Alkner, Sara}},
  issn         = {{1932-6203}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Plasma membrane expression of G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 (GPR30) is associated with worse outcome in metachronous contralateral breast cancer}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0231786}},
  doi          = {{10.1371/journal.pone.0231786}},
  volume       = {{15}},
  year         = {{2020}},
}

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Plasma membrane expression of G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 (GPR30) is associated with worse outcome in metachronous contralateral breast cancer