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

PLoS One. 2019 Dec 10;14(12):e0226150. doi: 10.1371/journal.pone.0226150. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Middle Aged
  • Prognosis
  • Tamoxifen / therapeutic use*

Substances

  • Antineoplastic Agents, Hormonal
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Tamoxifen

Grants and funding

This work was supported by the Swedish Breast Cancer Association (BRO, brostcancerforbundet.se)(S.A.); the Skåne University Hospital foundation (susforskningsmedel.skane.se) (S.A.); the Percy Falk Foundation (c/o Thomas Kramar, Sweden)(A.J.); Skåne County Council’s Research and Development Foundation (skane.se)(S.A.); and Governmental Funding of Clinical Research within the National Health Service (skane.se)(S.A.), Hans von Kantzow foundation (no URL)(A.J.), Allmänna Sjukhusets i Malmö stiftelse för bekämpande av cancer (cancerforskningmalmo.se)(A.J.), and O.E. and Edla Johansson’s foundation (oervetstiftelse.se)(A.J.). The funders had no role in study design, data collection, decision to publish, or preparation of the manuscript.