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Cancer Lett. 2019 Oct 1;461:21-30. doi: 10.1016/j.canlet.2019.06.011. Epub 2019 Jun 20.

Frequent amplifications of ESR1, ERBB2 and MDM4 in primary invasive lobular breast carcinoma.

Author information

1
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Obstetrics and Gynecology, The Third Xiangya Hospital, Central South University, Changsha, China; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
2
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
3
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
4
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology; University of Pittsburgh, Pittsburgh, PA, USA.
5
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
6
UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine, Division of Hematology Oncology; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
7
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Division of Surgical Oncology, Department of Surgery, Pittsburgh, PA, USA.
8
Division of Breast and Gynecologic Pathology, Department of Pathology, Pittsburgh, PA, USA.
9
Peter MacCallum Cancer Center, Melbourne, Australia.
10
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
11
Women's Cancer Research Center, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology; University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer following invasive ductal carcinoma (IDC). To identify potential genetic drivers of ILC progression, we used NanoString nCounter technology to investigate the DNA copy number (CN) in 70 well-curated primary ILC samples. We confirmed prior observations of frequent amplification of CCND1 (33%), and MYC (17%) in ILC, but additionally identified a substantial subset of ILCs with ESR1 and ERBB2 (19%) amplifications. Of interest, tumors with ESR1 CN gains (14%) and amplification (10%) were more likely to recur compared to those with normal CN. Finally, we observed that MDM4 (MDMX) was amplified in 17% of ILC samples. MDM4 knockdown in TP53 wild-type ILC cell lines caused increased apoptosis, decreased proliferation associated with cell cycle arrest, and concomitant activation of TP53 target genes. Similar effects were seen in TP53 mutant cells, indicting a TP53-independent role for MDM4 in ILC. To conclude, amplification of ESR1 and MDM4 are potential genetic drivers of ILC. These amplifications may represent actionable, targetable tumor dependencies, and thus have potential clinical implications and warrant further study.

KEYWORDS:

Amplification; ERBB2; ESR1; ILC; MDM4

PMID:
31229512
PMCID:
PMC6682463
[Available on 2020-10-01]
DOI:
10.1016/j.canlet.2019.06.011

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