Estrogen receptor-\u03b1 regulation of microRNA-590 targets FAM171A1\u2014a modifier of breast cancer invasiveness

Rahul Sanawar,Rakesh Kumar,Thankayyan R Santhoshkumar,M Radhakrishna Pillai,Vipin Mohan Dan

doi:10.1038/s41389-018-0113-z

Abstract

The pathobiology and aggressiveness of the triple negative breast cancer (TNBC) are influenced by genes that are preferentially expressed in TNBC cells. However, the nature of such genes with the role in invasiveness of TNBC cells is not fully understood. Here, we identified FAM171A1, member (A1) of the family with sequence similarity 171, as an overexpressed candidate gene in TNBC cells and tumors as compared to estrogen receptor-alpha (ERα) positive breast cancer. We found that the expression of FAM171A1 correlates well with the loss of ERα as well as its newly identified target miR590-5p in TNBC but not in ERα-positive cells. In addition, we report that ERα regulates FAM171A1 expression through a mechanism which involves ERα stimulation of miR590-5p expression via binding to its promoter, and in-turn, miR590-5p suppression of FAM171A1 expression. Further, we found that the levels of FAM171A1 correlate well with cancer cell aggressiveness as depletion or overexpression of FAM171A1 confers reduced or increased ability of TNBC cells to form mammospheres, respectively in accordance with the previous report of increased mammosphere formation potential of metastatic cells. In brief, results presented here have demonstrated that ERα regulation of FAM171A1 expression via miR590-5p explains the molecular basis of the noticed reduced levels of FAM171A1 in ER-positive breast cancer cells and that FAM171A1 is a preferably TNBC- overexpressed gene. Further, the noted loss of ERα–miR590-5p axis may upregulate the expression of FAM171A1 and consequently, resulting aggressiveness of TNBC cells. These findings suggest that FAM171A1 might represent a potentially novel therapeutic target for TNBC tumors.

Highlights

Breast cancer is the most common form of cancer in women[1]
Microarray expression profiles of breast cancer cell lines and breast tumor sub-types such as luminal and basal tumor tissues have been published recently[23]. We analyzed these data sets to identify the nature of unique genes that might be closely overexpressed in triple-negative breast cancer (TNBC) cells and TNBC breast tumors (Supplementary Fig. 1A). This strategy led us to a single gene, known as FAM171A1— which is widely expressed in the basal-like breast cancer cell lines and tissue samples
We found high levels of FAM171A1 in the basal-type TNBC cell lines such as MDA-MB-231, SUM149, SUM159, BT549, HCC1937, and Hs-578T as compared to non-TNBC breast cancer cell lines such as MCF-7, T47D, ZR-75, and SKBR3 as well as normal mammary epithelial cell line, HMEC (Fig. 1a–c, Supplementary 4A, B)

Summary

Introduction

Breast cancer is the most common form of cancer in women[1]. Despite significant advances in our ability to detect and treat breast cancer, it remains a leading cause of death in women with cancer, and the incidence of breast cancer continues to rise in many parts of the world. Triple-negative breast cancer (TNBC) sub-type is one of the aggressive breast cancers as TNBC cells lack all three currently targetable molecules such as estrogen receptor, progesterone receptor, and HER2. Previous work suggests that FAM171A1 may be associated with chemoresistance of cancer cells[2,3]. Datamining studies suggest that FAM171A1 interacts with

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Conclusion