Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER) positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy), the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer.

Breast cancer (BC) outcome is determined mainly by its ability to spread to distant sites, since this is the lethal phase of the disease. Metastasizing cells have to acquire various molecular aberrations in order to go through the metastatic cascade and gain organ tropism. These are probably reflected at the primary tumor. This study was aimed to identify a set of abnormally expressed proteins in primary human BC tumors, which spread preferentially to the liver or elsewhere. Methods: We collected archival paraffin embedded primary BC samples from 48 patients who were divided into 3 groups: 10 who developed liver metastases (A), 20 with metastases to other sites (B) and 18 with no BC recurrence (C). Tissue microarray (TMA) were constructed, sliced and subjected to immuno-histochemical staining. A pre-defined panel of 11 proteins was selected, based on published data that were available at the time of study initiation. Level of expression (coded by IRS scoring) and the intra/extracellular location of each protein was determined by an expert pathologist and compared between the three groups. The panel included: cell-cell interaction proteins (CDH1, BIGH3, MMP14, CD44s, Galectin-3), transcription factors (FRA-1, c-Jun, GATA-3, TP53), an inflammatory chemokine (CCL5), cell signaling protein (Wnt-5a). Results: Metastatic tropism to the liver was studied by comparing results between A and B. When similar, A and B were combined and compared with C group. CDH1 protein expression was significantly reduced in the cytoplasm in groups A and B in comparison to C (p=0.004)and over-expressed in the membrane (p<0.001) in both. Hence, cytoplasmic CDH1was higher in group A than B (p=0.03). In group A only, a trend of BIGH3 over-expression was noted, though it did not reach significance. No further differences were found between A versus B. MMP14 was over-expressed both in the membrane and cytoplasm (p=0.001) of A and B, in comparison with C. CD44s was over-expressed in the membrane in A&B versus C (p<0.001). Galectin-3 was over-expressed in the cytoplasm (p=0.005) and down regulated in the nucleus (p=0.015) in both metastatic groups. CCL5 (RANTES) level was significantly reduced in the cytoplasm in A & B (p<0.001) while significantly over-expressed in the nuclei (p=0.005). c-Jun (part of AP1 complex) was over-expressed in both A and B (p=0.021). On the other hand, levels of FRA-1, localized in both cytoplasm and nucleus in C, were reduced in both compartments in A & B (p=0.029). No difference was noted between the 3 groups in level and localization of TP53, GATA-3 and Wnt-5a. Conclusions: Assessment of the expression of proteins in tumor cells should include protein localization besides its level of expression. Both CDH1 and BIGH3 seem to be over-expressed in tumors that spread preferentially to the liver. No significant changes in pattern of expression of the other proteins studied could be correlated with metastatic propensity to the liver. Compartmental translocation of various proteins is correlated with the acquisition of metastatic potential, such as CDH1 and CCL5 which presented a shift from nucleus to cytoplasm, and Galectin-3 and CCL5, where translocation from cytoplasm to membrane were observed in both metastatic groups. Citation Format: Goldberg H, Fell R, Apel-Sarid L. Differential protein expression in primary breast cancer tumors spreading to liver or elsewhere [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-13-01.