Abstract
BackgroundAdjuvant 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.
Highlights
The majority of breast cancers express estrogen receptor α (ERα) [1], and adjuvant endocrine therapy significantly improves patient-survival
Breast tumors developed during adjuvant tamoxifen more often have high HIF1-α levels the National Health Service(S.A.), Hans von Kantzow foundation(A.J.), Allmanna Sjukhusets i Malmostiftelse for bekampande av cancer(A.J.), and O.E. and Edla Johansson’s foundation(A.J.)
We show here that an increased proportion of tamoxifen-resistant contralateral breast cancer (CBC), i.e. tumors developed during adjuvant tamoxifen treatment, were hypoxia-inducible factor (HIF)-1α positive and that HIF-1α-positivity in the tumors led to increased breast cancer mortality (BCM)
Summary
The majority of breast cancers express estrogen receptor α (ERα) [1], and adjuvant endocrine therapy significantly improves patient-survival. Tamoxifen is the most common adjuvant endocrine treatment in premenopausal women and reduces recurrences with about 50% [2] It is widely used for treatment of ERα-positive generalized breast cancer. We employ a novel approach to study endocrine therapy escape mechanisms in vivo in breast cancer patients by analyzing metachronous contralateral breast cancer (CBC), i.e. development of a second breast cancer (BC2) in the contralateral breast despite on-going adjuvant tamoxifen treatment given for the first tumor (BC1), and resistant to this treatment. 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. 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
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