Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma.
نویسندگان
چکیده
UNLABELLED Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant. SIGNIFICANCE NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies.
منابع مشابه
Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma Discovery of Biomarkers Predictive of GSI Response in
Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to con-stitutive receptor activation were confi ned to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secreta...
متن کاملA Case Report of Adenoid Cystic Carcinoma in Breast in Buali Hospital
SUMMARY An infrequent case of adenoid cystic carcinoma is described. Four years ago a 35 year old women was admitted to BuAli Hospital because of a firm painful mass near her left areola. The pathologic diagnosis after surgery was adenoid cystic carcinoma of breast. Up to now the patient is quite well without recurrence. incidence. Adenoid cystic carcinoma is an infrequent type of breast ...
متن کاملPredictive ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography for pathological complete response and prognosis after neoadjuvant chemotherapy in triple-negative breast cancer patients
Objective The mortality of patients with locally advanced triple-negative breast cancer (TNBC) is high, and pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved prognosis. This retrospective study was designed and powered to investigate the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to predict pat...
متن کاملAdenoid Cystic Carcinoma of the Breast A focused review
Adenoid cystic carcinoma is the most common epithelial malignancy of the minor salivary glands, where it follows an aggressive course with a strong predilection for metastases; by contrast, breast adenoid cystic carcinoma (bACC) represents only 0.1% of breast malignancies and has an indolent natural history with metastases occurring as an uncommon event. Identification of bACC is challenging, a...
متن کاملبررسی ایمونوهیستوشیمیائی Expression گیرنده پروژسترون در پلئومورفیک آدنوما و آدنوئیدسیستیک کارسینومای غده بزاقی
Background and Aim: The hormone receptor status in breast cancer has been pivotal in determining the likelihood of response to hormonal manipulation. Tumors which are both estrogen and progesterone receptor positive are much more likely to respond to anti-hormone therapy than negative tumors. There is well-established similarity between breast tissue and salivary glands. The aim of this study w...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer discovery
دوره 4 10 شماره
صفحات -
تاریخ انتشار 2014