PMID- 30367629
OWN - NLM
STAT- MEDLINE
DCOM- 20190606
LR  - 20240315
IS  - 1465-542X (Electronic)
IS  - 1465-5411 (Print)
IS  - 1465-5411 (Linking)
VI  - 20
IP  - 1
DP  - 2018 Oct 26
TI  - Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and 
      alters breast tumor growth.
PG  - 131
LID - 10.1186/s13058-018-1057-0 [doi]
LID - 131
AB  - BACKGROUND: Amphiregulin (AREG), a ligand of the epidermal growth factor 
      receptor, is not only essential for proper mammary ductal development, but also 
      associated with breast cancer proliferation and growth. In the absence of AREG, 
      mammary ductal growth is stunted and fails to expand. Furthermore, suppression of 
      AREG expression in estrogen receptor-positive breast tumor cells inhibits 
      in-vitro and in-vivo growth. METHODS: We crossed AREG-null (AREG(-/-)) mice with 
      the murine luminal B breast cancer model, MMTV-PyMT (PyMT), to generate 
      spontaneous breast tumors that lack AREG (AREG(-/-) PyMT). We evaluated tumor 
      growth, cytokeratin-8 (K8)-positive luminal cells, cytokeratin-14 (K14)-positive 
      myoepithelial cells, and expression of AREG, Ki67, and PyMT. Primary 
      myoepithelial cells from nontumor-bearing AREG(+/+) mice underwent 
      fluorescence-activated cell sorting and were adapted to culture for in-vitro 
      coculture studies with AT-3 cells, a cell line derived from C57Bl/6 PyMT mammary 
      tumors. RESULTS: Intriguingly, PyMT-induced lesions progress more rapidly in 
      AREG(-/-) mice than in AREG(+/+) mice. Quantification of K8(+) luminal and K14(+) 
      myoepithelial cells in non-PyMT AREG(-/-) mammary glands showed fewer K14(+) 
      cells and a thinner myoepithelial layer. Study of AT-3 cells indicated that 
      coculture with myoepithelial cells or exposure to AREG, epidermal growth factor, 
      or basic fibroblast growth factor can suppress PyMT expression. Late-stage 
      AREG(-/-) PyMT tumors are significantly less solid in structure, with more areas 
      of papillary and cystic growth. Papillary areas appear to be both less 
      proliferative and less necrotic. In The Cancer Genome Atlas database, luminal-B 
      invasive papillary carcinomas have lower AREG expression than luminal B invasive 
      ductal carcinomas. CONCLUSIONS: Our study has revealed a previously unknown role 
      of AREG in myoepithelial cell development and PyMT expression. AREG expression is 
      essential for proper myoepithelial coverage of mammary ducts. Both AREG and 
      myoepithelial cells can suppress PyMT expression. We find that lower AREG 
      expression is associated with invasive papillary breast cancer in both the 
      MMTV-PyMT model and human breast cancer.
FAU - Mao, Serena P H
AU  - Mao SPH
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
FAU - Park, Minji
AU  - Park M
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
FAU - Cabrera, Ramon M
AU  - Cabrera RM
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
FAU - Christin, John R
AU  - Christin JR
AD  - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
FAU - Karagiannis, George S
AU  - Karagiannis GS
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
AD  - Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
AD  - Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
FAU - Oktay, Maja H
AU  - Oktay MH
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
AD  - Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
AD  - Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
FAU - Zaiss, Dietmar M W
AU  - Zaiss DMW
AD  - Institute of Immunology and Infection Research, University of Edinburgh, 
      Edinburgh, UK.
FAU - Abrams, Scott I
AU  - Abrams SI
AD  - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      14263, USA.
FAU - Guo, Wenjun
AU  - Guo W
AD  - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
FAU - Condeelis, John S
AU  - Condeelis JS
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
AD  - Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
AD  - Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA.
FAU - Kenny, Paraic A
AU  - Kenny PA
AD  - Kabara Cancer Research Institute, Gundersen Medical Foundation, La Crosse, WI, 
      54601, USA.
FAU - Segall, Jeffrey E
AU  - Segall JE
AUID- ORCID: 0000-0001-5425-9315
AD  - Department of Anatomy and Structural Biology, Albert Einstein College of 
      Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. 
      Jeffrey.segall@einstein.yu.edu.
AD  - Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 
      10461, USA. Jeffrey.segall@einstein.yu.edu.
LA  - eng
GR  - MR/M011755/1/MRC_/Medical Research Council/United Kingdom
GR  - T32 GM007491/GM/NIGMS NIH HHS/United States
GR  - S10 OD019961/OD/NIH HHS/United States
GR  - T32 GM007288/GM/NIGMS NIH HHS/United States
GR  - P30 CA013330/CA/NCI NIH HHS/United States
GR  - CA100324/NH/NIH HHS/United States
GR  - P01 CA100324/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181026
PL  - England
TA  - Breast Cancer Res
JT  - Breast cancer research : BCR
JID - 100927353
RN  - 0 (Amphiregulin)
RN  - 0 (Antigens, Polyomavirus Transforming)
RN  - 0 (Areg protein, mouse)
SB  - IM
MH  - Amphiregulin/genetics/*metabolism
MH  - Animals
MH  - Antigens, Polyomavirus Transforming/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Epithelial Cells/*pathology/virology
MH  - Female
MH  - Humans
MH  - Mammary Glands, Animal/cytology/*pathology
MH  - Mammary Neoplasms, Experimental/genetics/*pathology/virology
MH  - Mammary Tumor Virus, Mouse/genetics/pathogenicity
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neoplasm Invasiveness/pathology
MH  - Polyomavirus/genetics/immunology
PMC - PMC6203982
OTO - NOTNLM
OT  - Amphiregulin
OT  - Breast cancer
OT  - MMTV-PyMT
OT  - Mammary ductal development
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The animal studies were completed in 
      line with our animal protocol with approval by the Institutional Animal Care and 
      Use Committee of the Albert Einstein College of Medicine. CONSENT FOR 
      PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they 
      have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral 
      with regard to jurisdictional claims in published maps and institutional 
      affiliations.
EDAT- 2018/10/28 06:00
MHDA- 2019/06/07 06:00
PMCR- 2018/10/26
CRDT- 2018/10/28 06:00
PHST- 2018/06/05 00:00 [received]
PHST- 2018/10/02 00:00 [accepted]
PHST- 2018/10/28 06:00 [entrez]
PHST- 2018/10/28 06:00 [pubmed]
PHST- 2019/06/07 06:00 [medline]
PHST- 2018/10/26 00:00 [pmc-release]
AID - 10.1186/s13058-018-1057-0 [pii]
AID - 1057 [pii]
AID - 10.1186/s13058-018-1057-0 [doi]
PST - epublish
SO  - Breast Cancer Res. 2018 Oct 26;20(1):131. doi: 10.1186/s13058-018-1057-0.