Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like "triple negative" cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that more than half of primary ER + PR + breast cancers contain an ER

Breast cancer can recur even decades after the primary therapy. Markers are needed to predict cancer progression and the risk of late recurrence. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), proliferation marker Ki-67, and cytokeratin CK5 were studied to find out whether their expression or occurrence in subgroups of breast cancers correlated with the time of recurrence. The expression of HER2, ER, PR, Ki-67, and CK5 was studied by IHC in 72 primary breast cancers and their corresponding recurrent/metastatic lesions. The patients were divided into three groups according to the time of the recurrence/metastasis: before two years, after 5 years, and after 10 years. Based on their IHC profiles, the tumors were divided into surrogates of the genetically defined subgroups of breast cancers and the subtype definitions were as follows: luminal A (ER or PR+HER2–), luminal B (ER or PR+HER2+), HER2 overexpressing (ER–PR–HER2+), triple-negative (ER–PR–HER2–), basal-like (ER–PR–HER2–CK5+), non-classified (ER–PR–HER2–CK5–) and luminobasal (ER or PR+CK5+). In multivariate analysis, tumor size and HER2 positivity were a significant risk of early cancer relapse. The metastases showed a significantly lower CK5 expression. CK5 positivity distinguished triple negative tumors into rapidly and slowly recurring cancers. The IHC subtype ER or PR+HER2– luminal A presented a significantly lower risk of early tumor recurrence. Ki-67 expression denoted early-relapsing tumors and correlated linearly with tumor progression, since Ki-67 positivity declined gradually from early-relapsing toward late-recurring cancers.

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IntroductionLuminal, estrogen receptor-positive (ER+) breast cancers can metastasize but lie dormant for years before recurrences prove lethal. Understanding the roles of estrogen (E) or progestin (P) in development of luminal metastases or in arousal from dormancy is hindered by few preclinical models. We have developed such models.MethodsImmunocompromised, ovariectomized (ovx’d) mice were intracardiac-injected with luminal or basal human breast cancer cells. Four lines were tested: luminal ER+PR+ cytokeratin 5-negative (CK5−) E3 and MCF-7 cells, basal ER−PR−CK5+ estrogen withdrawn-line 8 (EWD8) cells, and basal ER−PR−CK5− MDA-MB-231 cells. Development of micrometastases or macrometastases was quantified in ovx’d mice and in mice supplemented with E or P or both. Metastatic deposits were analyzed by immunohistochemistry for luminal, basal, and proliferation markers.ResultsER−PR− cells generated macrometastases in multiple organs in the absence or presence of hormones. By contrast, ovx’d mice injected with ER+PR+ cells appeared to be metastases-free until they were supplemented with E or E+P. Furthermore, unlike parental ER+PR+CK5− cells, luminal metastases were heterogeneous, containing a significant (6% to 30%) proportion of non-proliferative ER−PR−CK5+ cells that would be chemotherapy-resistant. Additionally, because these cells lack receptors, they would also be endocrine therapy-resistant. With regard to ovx’d control mice injected with ER+PR+ cells that appeared to be metastases-free, systematic pathologic analysis of organs showed that some harbor a reservoir of dormant micrometastases that are ER+ but PR−. Such cells may also be endocrine therapy- and chemotherapy-resistant. Their emergence as macrometastases can be triggered by E or E+P restoration.ConclusionsWe conclude that hormones promote development of multi-organ macrometastases in luminal disease. The metastases display a disturbing heterogeneity, containing newly emergent ER−PR− subpopulations that would be resistant to endocrine therapy and chemotherapy. Similar cells are found in luminal metastases of patients. Furthermore, lack of hormones is not protective. While no overt metastases form in ovx’d mice, luminal tumor cells can seed distant organs, where they remain dormant as micrometastases and sheltered from therapies but arousable by hormone repletion. This has implications for breast cancer survivors or women with occult disease who are prescribed hormones for contraception or replacement purposes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0489-4) contains supplementary material, which is available to authorized users.