Correlation between steroid hormone receptors and prognostic factors in human breast cancer

Knowledge of the tumor content of estrogen (ER) and progesterone (PgR) receptors has proved to be of significant value in human breast cancer. Relative determinations were performed in 589 specimens in our laboratory. The positivity of ER and PgR is correlated with the patients' age at diagnosis, tumor size and relative grade. In particular, the significance of PgR versus ER status and the possible prognostic role of these receptors are investigated.     

Biochemical and histochemical analysis of steroid hormone binding sites in human primary breast cancer

Mammary carcinoma tissue from 514 primary breast cancer patients were all biochemically and histochemically analyzed for both estrogen receptors and progesterone receptors. The dextran-coated charcoal (DCC) method measured the ER and PR as defined by Scatchard analysis, ligand competition experiments and target organ specificity. The ligands, estradiol-6-carboxymethyloxime-BSA-fluoresceine isothiocyanate and hydroxyprogesteronehemisuccinate-BSA-tetramethylrhodamine isothiocyanate, used for histochemistry, did not bind to either ER or PR and were mainly bound to the membrane fraction of isolated breast cancer cells. Fluorescence was not specifically inhibited by estrogens or progestogens. In addition, "estrogenic" always coincided with "progestogenic" fluorescence. The binding of the fluoresceine compounds to tissue slides depended on the large steroid hormone substitution on the bovine serum albumin molecule. Clinical parameters, known to be related to ER and PR did not correlate with the histochemical results. The observations indicated the impossibility of specific steroid receptor detection by the histochemical method. Therefore, up to the present, evaluation of hormone dependency and prognosis in human breast cancer cannot be based on this approach.     

类固醇激素在乳腺癌中的作用及对肿瘤干细胞的影响

类固醇激素尤其雌激素和孕激素在乳腺癌的发病、进展和治疗中起着重要作用。与此同时,大量的研究证实肿瘤干细胞在乳腺癌发生、进展和转移过程中也起着关键作用。在乳腺癌临床治疗中,尽管肿瘤细胞经过常规抗内分泌治疗后受到了明显的抑制,但仅需少量的乳腺肿瘤干细胞(Breast cancer stem cells,BCSCs)存在,仍可维持肿瘤的再生长。以往大量的研究多集中在激素对正常乳腺发育及其与乳腺癌的相关性方面,最近,更多的研究观察激素对乳腺肿瘤干细胞活性影响,这为乳腺癌治疗和肿瘤干细胞研究开辟了新的方向。本文全面讨论类固醇激素(雌激素和孕激素)在乳腺癌中的作用及其对乳腺肿瘤干细胞的活性调节。     

Benign mammary epithelial cells enhance the transformed phenotype of human breast cancer cells

Background  

Recent research has yielded a wealth of data underscoring the key role of the cancer microenvironment, especially immune and stromal cells, in the progression of cancer and the development of metastases. However, the role of adjacent benign epithelial cells, which provide initial cell-cell contacts with cancer cells, in tumor progression has not been thoroughly examined. In this report we addressed the question whether benign MECs alter the transformed phenotype of human breast cancer cells.     

Podocalyxin increases the aggressive phenotype of breast and prostate cancer cells in vitro through its interaction with ezrin

Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin.     

Multiple steroid receptors in human breast cancer

Summary Histopathologic features (tumor cell density, histological type, and histoprognostic grade) were analyzed in 314 breast cancers investigated for estrogen (E) and progestin (P) receptors (R). The presence of PR is associated with the presence of ER. A relationship was found between the acinoductal differentiation of the lesions and the presence of SR: the more differentiated the carcinoma, the higher the frequency of ER. HPG III carcinomas have the lowest frequency of positive ER and HPG I tumors the opposite: the likelihood of the presence of SRs is inversely correlated with HPG. No statistically significant relationship existed between tumor cell density (TCD) and the presence of ER or ER content. Similar findings were observed for the stromal reaction. The results are discussed with respect to the biological significance of SR and histopathologic features: SR presence could be correlated with (1) a differentiated state of the tumors and (2) a slow rate of cellular replication.     

Prolactin response to thyrotropin-releasing hormone in early and advanced human breast cancer

While prolactin (PRL) has been shown to stimulate the development of mammary carcinoma in several animal species, its role in human breast cancer remains to be established. To further investigate PRL secretion in human breast cancer, its basal levels and response to thyrotropin-releasing hormone (TRH) were evaluated in 16 patients (6 with no metastases and 10 with metastatic locations). The control group consisted of 19 healthy women. High PRL basal concentrations were seen in 2 patients only; no significant differences were found between the other patients and the normal subjects. The PRL increase induced by TRH administration was significantly higher in patients than in controls. Finally a change in the hormonal secretion was found after chemotherapy in 3 of the 5 patients in whom PRL response to TRH was evaluated either before or 10-12 days after a cycle of intravenous CMF adjuvant chemotherapy. These results demonstrate the existence of an exaggerated response of PRL to TRH in patients with breast cancer, even in the presence of normal basal levels. Moreover, they would seem to suggest a possible influence of CMF on PRL response to TRH stimulation.     

The response of breast cancer cells to steroid and peptide growth factors.

Four breast cancer cell lines covering a wide range of receptor characteristics were examined for their growth responses to oestradiol, insulin, EGF and the anti-oestrogen, tamoxifen. Stimulated cellular growth using both the MTT assay and 3H-thymidine incorporation into DNA, was measured against controls grown in a steroid reduced environment. The ER positive MCF-7 cell line showed clear growth responses to E2, insulin and EGF. This was also demonstrated, although to a lesser extent in the ZR-75-1 line which expresses lower levels of ER. In combination, these factors gave an additive growth response but the addition of EGF to maximal concentrations of insulin and oestradiol produced no further increase in growth. In contrast to these results, the two ER negative cell lines examined, MCF-7 Adr and MDA-MB-231 showed no growth response to exogenously applied steroids and in the case of MCF-7 Adr high concentrations of EGF were able to inhibit the growth of this cell line. They also showed high rates of growth in a steroid depleted environment which tends to suggest these cells are growing autonomously through autocrine growth factor induction.     

Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer

Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR, respectively.     

CORRELATION OF STEROID HORMONE RECEPTORS AND CLINICAL PATHOLOGICAL FEATURES WITH PROGNOSIS OF HUMAN BREAST CANCER

Clinical, pathological features and steroid hormone receptors (SR) including receptors of estrogen (ER), progesterone (PR) and androgen (AR) were observed in 58 cases of breast carcinoma, and related to patient 5- year survival rate through stratification and multivariatc analysis. The results showed that histologic tumor type and grading, lymphnode status, ER value and patient age took more important role in patient survival, and SR, especially, conferred survival advantage in advanced cases with tumor size larger than 2 cm, node involved, or TNM Stage Ⅱ-Ⅲ.