Increase In Estrogen Receptor Expression Research Articles

Abstract P1-14-02: Neoadjuvant letrozole and lapatinib is feasible in Asian postmenopausal women with estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER-2) positive breast cancer [Neo-All-In]: First efficacy and safety report

Abstract Purpose Neo-ALL-In (NCT 01275859) is a single center, prospective study aimed to evaluate the recruitment feasibility, efficacy and safety profiles as well as biologic features of neoadjuvant letrozole plus lapatinib in postmenopausal women with ER and HER2 positive breast cancer. Methods Postmenopausal women with stage IIA to IIIB ER and HER-2 positive breast cancer were eligible. Patients received combination therapy of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily for 18-21 weeks before surgery. Clinical responses were assessed by clinical palpation, ultrasonography (US), mammography and/or MRI. Tissue and/or blood samples were collected for analysis of biomarkers at three time points (baseline, day 15, and before surgery). Baseline Fluorine-18 Fluorodeoxyglucose (18F-FDG) and Fluorine-18 Fluoroestradiol (18F-FES) PET-CT imagings were obtained. Results Among twenty-four patients enrolled, 22 patients underwent surgery while 1 patient is currently on neoadjuvant therapy and the other patient is waiting for surgery. Among 22 patients completed surgery, 16 patients (72.7%) completed planned neoadjuvant letrozole and lapatinib, whereas 3 patients (13.6%) prematurely terminated the treatment and proceeded to surgery due to minimal clinical response or progression. Except grade 3 liver toxicities revealed in 3 patients (13.6%), which resulted in sequential dose reduction and discontinuation, adverse events were mainly grades 1 to 2 (Skin, 83.3%; GI, 77.3%), and these were generally tolerable with excellent compliance. Overall clinical response rates including complete and partial response was 72.7% (n=16), and pathologic complete response in breast (pCR; ypT0-is) was 4.5% (n=1). Clinical and pathologic responses of 22 patients by assessment modalitiesTotal (N=22, %)Clinical palpationUSMammographyMRpathologic response in breast (ypT0-is)pathologic response in breast and lymph nodes (ypT0-is N0)Overall responseCR1 (4.5)0 (0.0)0 (0.0)1 (4.5)1 (4.5)0 (0.0)1 (4.5)PR17 (77.3)12 (54.5)9 (40.9)9 (40.9)11 (50.0)15 (68.215 (68.2)No change3 (13.6)9 (40.9)13 (59.1)5 (22.7)9 (40.9)7 (31.8)4 (18.2)PD1(4.5)1 (4.5)0 (0.0)1 (4.5)1 (4.5)0 (0.0)2 (9.1)Not available/evaluable0 (0.0)0 (0.0)0 (0.0)6 (27.3)0 (0.0)0 (0.0)0 (0.0)CR, complete response; PR, partial response; PD, progressive disease; US, ultrasonography In analyses of biomarkers thus far, 81.8% of patients showed stationary expression of HER-2, 54.5% of patients showed decrease in Ki-67 expression, and 27.3% of patients showed increase in ER expression from baseline to surgery by immunothistochemistry (IHC) staining. Decreased expression of ER after surgery by IHC staining was significantly correlated with poor clinical response (p=0.004). However, no significant differences in baseline SUVmax in FDG-PET were found between responders and non-responders (8.8 VS 10.7, p=0.53). Conclusion This chemo-free combination neoadjuvant therapy was feasible, with comparable efficacy outcomes and manageable toxicities profiles. Updated data on 18F-FES PET-CT and biomarkers will be provided. Citation Format: Ji Hyun Park, Myoung Joo Kang, Jin-Hee Ahn, Jeong Eun Kim, Kyung Hae Jung, Gyung-Yub Gong, Hee Jin Lee, Byung-Ho Son, Sei-Hyun Ahn, Hak-Hee Kim, Hee Jung Shin, Dae-Hyuk Moon, Sung-Bae Kim. Neoadjuvant letrozole and lapatinib is feasible in Asian postmenopausal women with estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER-2) positive breast cancer [Neo-All-In]: First efficacy and safety report [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-14-02.

Abstract P1-12-14: Retinoic acid sensitizes triple-negative breast cancer cells to tamoxifen treatment

Abstract Tamoxifen, an estrogen receptor (ER) antagonist, is often used as an adjuvant endocrine therapy in the successful treatment of ER+ breast tumors. Tumors that lack ER, progesterone receptor (PR) and HER2 expression (i.e. triple-negative breast cancers) cannot be treated with adjuvant endocrine therapies, like tamoxifen, and are often more aggressive. Inducing ER expression is a potential strategy for sensitization of triple-negative breast cancers to adjuvant endocrine therapies. Given recent evidence suggesting cross-talk between the retinoic acid (RA) and estrogen signaling pathways, we investigated if RA induces expression of ER in triple-negative breast cancer cells. We hypothesize that this would lead to sensitization of the cells to tamoxifen treatment. Quantitative PCR of mRNA isolated from triple-negative MDA-MB-231 cells treated with RA and estradiol had increased ER transcript levels. Furthermore, treatment with estradiol and RA synergistically induced increased expression of RA-inducible genes. In cell proliferation studies, neither RA nor estradiol treatment alone significantly altered the growth of MDA-MB-231 cells; however, when treated with both estradiol and RA together, the growth of the cells increased significantly. This suggests that the RA-mediated increase in ER expression sensitizes MDA-MB-231 cells to estradiol-induced cell growth. Next, we investigated whether the increased ER expression sensitized MDA-MB-231 cells to tamoxifen treatment. Tamoxifen did not decrease the growth of MDA-MB-231 cells; however, when applied in combination with both estradiol and RA, tamoxifen significantly reduced MDA-MB-231 proliferation. Furthermore, tamoxifen treatment reduced the synergistic effects of estradiol/RA on RA-inducible gene expression. Together, these results suggest that the use of RA in combination with tamoxifen warrants further investigation as a potential treatment for triple-negative breast cancers. The success of the combination treatment of tamoxifen and RA in the reduction of triple-negative breast cancer cell tumor xenografts will provide further justification for this strategy in the treatment of triple-negative breast cancers. Citation Format: Krysta M Coyle, Cheryl A Dean, Diana B Jo, Margaret Thomas, Mohammad Sultan, Paola Marcato. Retinoic acid sensitizes triple-negative breast cancer cells to tamoxifen treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-14.

Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.

Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.

Effects of perfluorooctanesulfonate and perfluorobutanesulfonate on the growth and sexual development of Xenopus laevis

Perfluorobutanesulfonate (PFBS), as a substitute for perfluorooctanesulfonate (PFOS), is widespread in the environment and biotic samples as well as PFOS. To investigate effects of PFOS and PFBS on the growth and sexual development of amphibians, we exposed Xenopus laevis tadpoles at a series of concentrations of PFOS and PFBS (0.1; 1; 100; 1,000 μg/l) as well as 17-beta-estradiol (E2, 100 ng/l) and 5 alpha-androstan-17-beta-ol-3-one (DHT, 100 ng/l) from stage 46/47 to 2 months postmetamorphosis. We found that neither PFOS nor PFBS had a significant effect on the survival and growth. However, they caused hepatohistological impairment at higher concentrations (100; 1,000 μg/l). Unlike E2, PFOS at all concentrations did not alter the sex ratio and induce intersex, but caused degeneration of spermatogonia in testes except for the lowest concentration. PFBS had no effect on the sex ratio and gonadal histology. PFOS and PFBS promoted expression of estrogen receptor (ER) and androgen receptor (AR), but not affected aromatase expression in the brain. The increase in expression of ER and AR suggests an increase in the responsiveness to the corresponding sex hormone and potential effects on sexual development. Our results show that PFBS as well as PFOS have adverse effects on hepato-histology and sexual development on X. laevis. Also, PFOS- and PFBS-induced increase in ER and AR expression highlights the need to further study effects of PFOS and PFBS on subsequently gonadal development, sexual dimorphism, and secondary sex characteristics in X. laevis. It is debatable that PFBS is widely used as a substitute of PFOS.

Effect of Yikun Neiyi Wan on the Expression of Aromatase P450, COX-2, and ER Related Receptor in Endometrial Cells in Vitro from Patients with Endometriosis

To investigate the effect of yikun neiyi wan (YKNYW) and gestrinone on the expression of aromatase P450 (P450arom), cyclo-oxygenase-2 (COX-2) and estrogen receptor (ER) in isolated ectopic and normal endometrial stroma cells in vitro. Digestion and serial filtration were used to isolate and culture the ectopic and eutopic endometrial cells from patients with chocolate cyst in virto. Transformation of the cell morphology was observed in a inverted microscope. The effect of YKNYW on the expression of aromatase P450, cyclo-oxygenase-2, estrogen receptor in cultured endometriosis cells were detected by immunohistochemical method. The expression levels of P450arom, COX-2 in glandular epithelium cells in vitro were decreased significantly by YKNYW compared with gestrinone (P < 0.05). ER expression in mesenchymal cells of endometriosis was increased by YKNYW in the large and medium dosage groups compared with gestrinone. The mechanism by which YKNYW alleviates endometriosis pain is possibly related to the decrease in ectopic endometrial P450 arom and COX-2 expression in glandular epithelium, contrary to gestrinone, and the increase in ER expression in mesenchymalis, consistent with gestrione in patients with endometriosis.