Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer

Autoři: Annika Jögi aff001;  Anna Ehinger aff002;  Linda Hartman aff002;  Sara Alkner aff002
Působiště autorů: Department of Laboratory Medicine, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden aff001;  Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund, Sweden aff002;  Lund University, Department of Clinical Genetics and Pathology, Medical Service, Regional Laboratories, Lund, Sweden aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article



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.


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.


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.


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.

Klíčová slova:

Breast cancer – Cancer detection and diagnosis – Cancer treatment – Endocrine therapy – Hypoxia – Immunologic adjuvants – Medical hypoxia – Prognosis


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2019 Číslo 12
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