Loss of primary cilia occurs early in breast cancer development.

Ina Menzl,Frank W Li,Ritu Pandey,Karen Weihs,Ray Nagle,Lauren Lebeau,Kimberly M Mcdermott,Nadia B Hassounah

doi:10.1186/2046-2530-3-7

Ina Menzl, Frank W Li + Show 6 more

Open Access

https://doi.org/10.1186/2046-2530-3-7

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Abstract

BackgroundPrimary cilia are microtubule-based organelles that protrude from the cell surface. Primary cilia play a critical role in development and disease through regulation of signaling pathways including the Hedgehog pathway. Recent mouse models have also linked ciliary dysfunction to cancer. However, little is known about the role of primary cilia in breast cancer development. Primary cilia expression was characterized in cancer cells as well as their surrounding stromal cells from 86 breast cancer patients by counting cilia and measuring cilia length. In addition, we examined cilia expression in normal epithelial and stromal cells from reduction mammoplasties as well as histologically normal adjacent tissue for comparison.ResultsWe observed a statistically significant decrease in the percentage of ciliated cells on both premalignant lesions as well as in invasive cancers. This loss of cilia does not correlate with increased proliferative index (Ki67-positive cells). However, we did detect rare ciliated cancer cells present in patients with invasive breast cancer and found that these express a marker of basaloid cancers that is associated with poor prognosis (Cytokeratin 5). Interestingly, the percentage of ciliated stromal cells associated with both premalignant and invasive cancers decreased when compared to stromal cells associated with normal tissue. To understand how cilia may be lost during cancer development we analyzed the expression of genes required for ciliogenesis and/or ciliary function and compared their expression in normal versus breast cancer samples. We found that expression of ciliary genes were frequently downregulated in human breast cancers.ConclusionsThese data suggest that primary cilia are lost early in breast cancer development on both the cancer cells and their surrounding stromal cells.

Highlights

Primary cilia are microtubule-based organelles that protrude from the cell surface
We examined the frequency of primary cilia on breast cancer cells by staining tumor samples from 39 patients with pre-malignant carcinoma in situ (CIS) and from 65 patients with invasive breast carcinoma (INV)
The Hematoxylin and Eosin (H&E) slide was used as a reference to find the tissue types of interest on the adjacent serial section, which was stained with antibodies recognizing acetylated tubulin (Ac-Tub) to visualize primary cilia and γ-tubulin (γ-Tub) to identify their associated centrosomes (Figure 1A and 1B)

Summary

Introduction

Primary cilia are microtubule-based organelles that protrude from the cell surface. Primary cilia play a critical role in development and disease through regulation of signaling pathways including the Hedgehog pathway. Little is known about the role of primary cilia in breast cancer development. Cilia expression has been analyzed in some human cancers, demonstrating that pancreatic cancer, renal cell carcinoma, cholangiocarcinoma, melanoma, ovarian cancer, and prostate cancer all have a general loss of cilia [8,9,10,11,12,13,14]. These studies suggest that loss of cilia may promote cancer development in some tissues. In order to better understand the role of cilia in cancer and targeted drug efficacy, it is critical to have a comprehensive analysis of cilia expression in all human cancers

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