Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer.
BACKGROUND:Adjuvant endocrine treatment improves survival after estrogen receptor (ER) positive breast cancer. Recurrences occur, and most patients with metastatic breast cancer develop treatment resistance and incurable disease. An influential factor in relation to endocrine treatment resistance is...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0226150 |
| _version_ | 1818403343860498432 |
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| author | Annika Jögi Anna Ehinger Linda Hartman Sara Alkner |
| author_facet | Annika Jögi Anna Ehinger Linda Hartman Sara Alkner |
| author_sort | Annika Jögi |
| collection | DOAJ |
| description | BACKGROUND:Adjuvant endocrine treatment improves survival after estrogen receptor (ER) positive breast cancer. Recurrences occur, and most patients with metastatic breast cancer develop treatment resistance and incurable disease. An influential factor in relation to endocrine treatment resistance is tumor hypoxia and the hypoxia inducible transcription factors (HIFs). Poor perfusion makes tumors hypoxic and induces the HIFs, which promote cell survival. We previously showed that hypoxic breast cancer cells are tamoxifen-resistant, and that HIF-inhibition restored tamoxifen-sensitivity. We found that HIF-induced tamoxifen-resistance involve cross-talk with epithelial growth factor receptor (EGFR), which itself is linked to tamoxifen resistance. Contralateral breast cancer (CBC), i.e. development of a second breast cancer in the contralateral breast despite adjuvant tamoxifen treatment is in essence a human in vivo-model for tamoxifen-resistance that we explore here to find molecular pathways of tamoxifen-resistance. METHODS:We constructed a tissue-microarray including tumor-tissue from a large well-defined cohort of CBC-patients, a proportion of which got their second breast cancer despite ongoing adjuvant therapy. Using immunohistochemistry >500 patients were evaluable for HIF-1α and EGFR in both tumors, and correlations to treatment, patient outcome, prognostic and predictive factors were analyzed. RESULTS:We found an increased proportion of HIF-1α-positive tumors in tamoxifen-resistant (CBC during adjuvant tamoxifen) compared to naïve tumors (CBC without prior tamoxifen). Tumor HIF-1α-positivity correlated to increased breast cancer mortality, and negative prognostic factors including low age at diagnosis and ER-negativity. There was a covariance of HIF-1α- and EGFR-expression and also EGFR-expression correlated to poor prognosis. CONCLUSIONS:The increased percentage of HIF-1α-positive tumors formed during adjuvant tamoxifen suggests a role for HIF-1α in escaping tamoxifen's restraining effects on breast cancer. Implicating a potential benefit of HIF-inhibitors in targeting breast cancers resistant to endocrine therapy. |
| first_indexed | 2024-12-14T08:22:45Z |
| format | Article |
| id | doaj.art-a2d1b0095bd84a58b5f1d33da548fb32 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T08:22:45Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a2d1b0095bd84a58b5f1d33da548fb322022-12-21T23:09:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-011412e022615010.1371/journal.pone.0226150Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer.Annika JögiAnna EhingerLinda HartmanSara AlknerBACKGROUND:Adjuvant endocrine treatment improves survival after estrogen receptor (ER) positive breast cancer. Recurrences occur, and most patients with metastatic breast cancer develop treatment resistance and incurable disease. An influential factor in relation to endocrine treatment resistance is tumor hypoxia and the hypoxia inducible transcription factors (HIFs). Poor perfusion makes tumors hypoxic and induces the HIFs, which promote cell survival. We previously showed that hypoxic breast cancer cells are tamoxifen-resistant, and that HIF-inhibition restored tamoxifen-sensitivity. We found that HIF-induced tamoxifen-resistance involve cross-talk with epithelial growth factor receptor (EGFR), which itself is linked to tamoxifen resistance. Contralateral breast cancer (CBC), i.e. development of a second breast cancer in the contralateral breast despite adjuvant tamoxifen treatment is in essence a human in vivo-model for tamoxifen-resistance that we explore here to find molecular pathways of tamoxifen-resistance. METHODS:We constructed a tissue-microarray including tumor-tissue from a large well-defined cohort of CBC-patients, a proportion of which got their second breast cancer despite ongoing adjuvant therapy. Using immunohistochemistry >500 patients were evaluable for HIF-1α and EGFR in both tumors, and correlations to treatment, patient outcome, prognostic and predictive factors were analyzed. RESULTS:We found an increased proportion of HIF-1α-positive tumors in tamoxifen-resistant (CBC during adjuvant tamoxifen) compared to naïve tumors (CBC without prior tamoxifen). Tumor HIF-1α-positivity correlated to increased breast cancer mortality, and negative prognostic factors including low age at diagnosis and ER-negativity. There was a covariance of HIF-1α- and EGFR-expression and also EGFR-expression correlated to poor prognosis. CONCLUSIONS:The increased percentage of HIF-1α-positive tumors formed during adjuvant tamoxifen suggests a role for HIF-1α in escaping tamoxifen's restraining effects on breast cancer. Implicating a potential benefit of HIF-inhibitors in targeting breast cancers resistant to endocrine therapy.https://doi.org/10.1371/journal.pone.0226150 |
| spellingShingle | Annika Jögi Anna Ehinger Linda Hartman Sara Alkner Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. PLoS ONE |
| title | Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. |
| title_full | Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. |
| title_fullStr | Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. |
| title_full_unstemmed | Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. |
| title_short | Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. |
| title_sort | expression of hif 1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer |
| url | https://doi.org/10.1371/journal.pone.0226150 |
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