Basal Protein Expression Is Associated With Worse Outcome and Trastuzamab Resistance in HER2+ Invasive Breast Cancer.

Autor: Chung A; Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: alice.chung@cshs.org., Choi M; Cedars-Sinai Medical Center, Los Angeles, CA., Han BC; Cedars-Sinai Medical Center, Los Angeles, CA., Bose S; Cedars-Sinai Medical Center, Los Angeles, CA., Zhang X; Cedars-Sinai Medical Center, Los Angeles, CA., Medina-Kauwe L; Cedars-Sinai Medical Center, Los Angeles, CA., Sims J; Cedars-Sinai Medical Center, Los Angeles, CA., Murali R; Cedars-Sinai Medical Center, Los Angeles, CA., Taguiam M; Cedars-Sinai Medical Center, Los Angeles, CA., Varda M; Cedars-Sinai Medical Center, Los Angeles, CA., Schiff R; Baylor College of Medicine, Houston, TX., Giuliano A; Cedars-Sinai Medical Center, Los Angeles, CA., Cui X; Cedars-Sinai Medical Center, Los Angeles, CA.
Jazyk: angličtina
Zdroj: Clinical breast cancer [Clin Breast Cancer] 2015 Dec; Vol. 15 (6), pp. 448-457.e2. Date of Electronic Publication: 2015 Jun 19.
DOI: 10.1016/j.clbc.2015.06.001
Abstrakt: Background: We investigated the effect of basal protein expression on trastuzamab response in patients with HER2-positive (HER2(+)) breast cancer who received trastuzamab (T) and in HER2(+) breast cancer cell lines.
Patients and Methods: Expression of cytokeratin (CK) 5/6, CK14, and epidermal growth factor receptor (EGFR) was evaluated after immunohistochemical staining in paraffin-embedded tissue of 97 patients with stage I to III HER2(+) breast cancer treated with chemotherapy/T. Groups with and without basal protein expression were compared with respect to clinicopathologic parameters and survival. We treated 4 cell lines (2 basal-HER2 [HCC1569, HCC1954] and 2 nonbasal HER2 [BT474, SKBR3]) each with vehicle, T 20 μg/mL, paclitaxel 0.01 μM (P), and T with P (T + P). Cell viability was assessed and HER2 pathway suppression was compared between groups using immunoblot analysis. Mammosphere formation was used to assess breast cancer stem cell properties.
Results: EGFR expression was significantly associated with cancer-specific survival (CSS) (P = .05). CK5/6 expression strongly correlated with overall and disease-free survival, and CSS (P = .03, P = .04, and P = .03, respectively). Statistical significance was maintained for EGFR and CK5/6 after adjustment for covariates. CK14 was not associated with survival. All cell lines expressed similar levels of HER2. T and P alone inhibited proliferation of nonbasal cell lines; T + P had an additive cytotoxic effect. Basal cells were resistant to T, P inhibited proliferation, but T + P had no additive cytotoxic effect on cell growth in basal cells. Immunoblot analysis showed a significant decrease in phosphorylated Akt levels after treatment with T or T + P in nonbasal cells but not in basal cells. Akt blockade suppressed growth of basal and nonbasal HER2(+) cells. Furthermore, basal HER2 cell lines had increased mammosphere formation, which suggests increased stem cell properties compared with nonbasal HER2 cell lines.
Conclusion: CK5/6 and EGFR expression are predictive of worse prognosis in HER2(+) breast cancer patients treated with T. Basal HER2 breast cancer cell lines are resistant to trastuzamab, which is mediated through the Akt pathway; AKT inhibition abrogates this resistance. Basal HER2 cell lines also have increased stem cell properties, which might play a role in the resistance pathway.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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