Identification of Specific miRNA Signature in Paired Sera and Tissue Samples of Indian Women with Triple Negative Breast Cancer

Abstract

Of several subtypes of breast cancer, triple negative breast cancer (TNBC) is a highly aggressive tumor that lacks expression of hormone receptors for estrogen, progesterone and human epidermal growth factor receptor 2 and shows a worst prognosis. The small noncoding RNAs (miRNAs) considered as master regulator of gene expression play a key role in cancer initiation, progression and drug resistance and have emerged as attractive molecular biomarkers for diagnosis, prognosis and treatment targets in cancer. We have done expression profiling of selected miRNAs in paired serum and tissue samples of TNBC patients and corresponding cell lines and compared with that of other subtypes, in order to identify novel serum miRNA biomarkers for early detection and progression of TNBC. A total of 85 paired tumor tissues and sera with an equal number of adjacent normal tissue margins and normal sera from age matched healthy women including tissue and sera samples from 15 benign fibroadenomas were employed for the study. We report for the first time an extremely high prevalence (73.9%) of TNBC in premenopausal women below 35 years of age and a significant altered expression of a panel of three specific oncogenic miRNAs- miR-21, miR-221, miR-210, and three tumor suppressor miRNAs- miR-195, miR-145 and Let-7a in both tissues and corresponding sera of TNBC patients when compared with triple positive breast cancer (TPBC) patients. While miR-21, miR-221 and miR-210 showed significant over-expression, miR-195 and miR-145 were downregulated and well correlated with various clinicopathological and demographic risk factors, tumor grade, clinical stage and hormone receptor status. Interestingly, despite being a known tumor suppressor, Let-7a showed a significant overexpression in TNBCs. It is suggested that this panel of six miRNA signature may serve as a minimally invasive biomarker for an early detection of TNBC patients.

Are Basal-Like and Non-Basal-Like Triple-Negative Breast Cancers Really Different?

“…Our study includes 200 cases of TNBC with a mean age of 49.7 years. is may be considered as younger age and is comparable to other Indian studies [4,6]. In contrast to this, older age at diagnosis was observed in Western studies [16,17].…”

“…Prevalence of TNBC in India is considerably higher compared with Western populations [4,5]. e recent literature reports an exceptionally high frequency of TNBC (73.9%) in Indian premenopausal women below 35 years of age, in the prime of their reproductive life [6].…”

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

“…The let-7 family of miRNAs is comprised of 12 members (48), targeting multiple oncogenes, including c-MYC and RAS (49), and are known to function as tumor suppressors (50,51). However, recent studies suggest that this family may also have a potential oncogenic role (52,53). Upregulation of let-7d has been linked to progression of ductal carcinoma in situ to invasive carcinoma ("invasiveness microsignature") (17).…”

Microparticle parking and isolation for highly sensitive microRNA detection

“…For example, the first dysregulation pattern shown in figure 5b (increased let-7a and miR145 expression, decreased miR221 expression) has been observed in metabolic diseases including type 2 diabetes mellitus and obesity 51–54 . Although the relative expression of different miRNAs may vary between studies due to differences in cell type, patient cohort, and disease stage or subtype, the three miRNA species we studied (let-7a, miR145, and miR221) have also been shown to have diagnostic value for prostate cancer 55 and triple negative breast cancer 56 . In figure 5, + sign represents 1 amol of spiked-in target, an amount which is nearly undetectable by direct tagging, but is clearly distinguishable from negative controls (- sign) in our demonstration.…”