PMID- 36914836
OWN - NLM
STAT- MEDLINE
DCOM- 20230417
LR  - 20240402
IS  - 1546-1718 (Electronic)
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 55
IP  - 4
DP  - 2023 Apr
TI  - Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis.
PG  - 595-606
LID - 10.1038/s41588-023-01298-x [doi]
AB  - Women with germline BRCA1 mutations (BRCA1(+/mut)) have increased risk for 
      hereditary breast cancer. Cancer initiation in BRCA1(+/mut) is associated with 
      premalignant changes in breast epithelium; however, the role of the 
      epithelium-associated stromal niche during BRCA1-driven tumor initiation remains 
      unclear. Here we show that the premalignant stromal niche promotes epithelial 
      proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell 
      RNA sequencing analysis of human preneoplastic BRCA1(+/mut) and noncarrier breast 
      tissues, we show distinct changes in epithelial homeostasis including increased 
      proliferation and expansion of basal-luminal intermediate progenitor cells. 
      Additionally, BRCA1(+/mut) stromal cells show increased expression of 
      pro-proliferative paracrine signals. In particular, we identify 
      pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors 
      including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven 
      tumorigenesis in vivo. Together, our findings demonstrate that precancerous 
      stroma in BRCA1(+/mut) may elevate breast cancer risk through the promotion of 
      epithelial proliferation and an accumulation of luminal progenitor cells with 
      altered differentiation.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
FAU - Nee, Kevin
AU  - Nee K
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Ma, Dennis
AU  - Ma D
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Nguyen, Quy H
AU  - Nguyen QH
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Pein, Maren
AU  - Pein M
AUID- ORCID: 0000-0002-7906-5960
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Pervolarakis, Nicholas
AU  - Pervolarakis N
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
AD  - Center for Complex Biological Systems, University of California, Irvine, CA, USA.
FAU - Insua-Rodriguez, Jacob
AU  - Insua-Rodriguez J
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Gong, Yanwen
AU  - Gong Y
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
AD  - Center for Complex Biological Systems, University of California, Irvine, CA, USA.
FAU - Hernandez, Grace
AU  - Hernandez G
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Alshetaiwi, Hamad
AU  - Alshetaiwi H
AUID- ORCID: 0000-0003-3144-7377
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
AD  - Department of Pathology, University of Hail, Hail, Saudi Arabia.
FAU - Williams, Justice
AU  - Williams J
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Rauf, Maha
AU  - Rauf M
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Dave, Kushal Rajiv
AU  - Dave KR
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Boyapati, Keerti
AU  - Boyapati K
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Hasnain, Aliza
AU  - Hasnain A
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Calderon, Christian
AU  - Calderon C
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Markaryan, Anush
AU  - Markaryan A
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA.
FAU - Edwards, Robert
AU  - Edwards R
AD  - Department of Pathology and Laboratory Medicine, University of California Irvine 
      Medical Center, Orange, CA, USA.
FAU - Lin, Erin
AU  - Lin E
AD  - Department of Surgery, University of California Irvine Medical Center, Orange, 
      CA, USA.
FAU - Parajuli, Ritesh
AU  - Parajuli R
AD  - Department of Surgery, University of California Irvine Medical Center, Orange, 
      CA, USA.
FAU - Zhou, Peijie
AU  - Zhou P
AD  - Department of Mathematics, University of California, Irvine, CA, USA.
AD  - The NSF-Simons Center for Multiscale Cell Fate Research, University of 
      California, Irvine, CA, USA.
FAU - Nie, Qing
AU  - Nie Q
AUID- ORCID: 0000-0002-8804-3368
AD  - Department of Mathematics, University of California, Irvine, CA, USA.
AD  - The NSF-Simons Center for Multiscale Cell Fate Research, University of 
      California, Irvine, CA, USA.
FAU - Shalabi, Sundus
AU  - Shalabi S
AUID- ORCID: 0000-0002-8440-2474
AD  - Beckman Research Institute at City of Hope, Duarte, CA, USA.
FAU - LaBarge, Mark A
AU  - LaBarge MA
AUID- ORCID: 0000-0003-2405-4719
AD  - Beckman Research Institute at City of Hope, Duarte, CA, USA.
FAU - Kessenbrock, Kai
AU  - Kessenbrock K
AUID- ORCID: 0000-0003-0410-6104
AD  - Department of Biological Chemistry, University of California, Irvine, CA, USA. 
      kai.kessenbrock@uci.edu.
LA  - eng
GR  - R01 CA234496/CA/NCI NIH HHS/United States
GR  - T32 CA009054/CA/NCI NIH HHS/United States
GR  - K99 CA267160/CA/NCI NIH HHS/United States
GR  - F30 CA243419/CA/NCI NIH HHS/United States
GR  - T32 GM008620/GM/NIGMS NIH HHS/United States
GR  - P30 CA062203/CA/NCI NIH HHS/United States
GR  - R00 CA181490/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20230313
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (BRCA1 Protein)
RN  - 0 (BRCA1 protein, human)
SB  - IM
CIN - Nat Rev Cancer. 2023 Jun;23(6):349. PMID: 37101004
MH  - Female
MH  - Humans
MH  - Mutation
MH  - BRCA1 Protein/genetics
MH  - *Breast Neoplasms/pathology
MH  - Cell Transformation, Neoplastic/metabolism
MH  - *Mammary Glands, Human/metabolism
MH  - Carcinogenesis/pathology
MH  - Stromal Cells/pathology
PMC - PMC10655552
MID - NIHMS1930037
COIS- Competing interests All the other authors declare no competing interests.
EDAT- 2023/03/15 06:00
MHDA- 2023/04/17 06:41
PMCR- 2024/04/01
CRDT- 2023/03/14 00:45
PHST- 2022/03/06 00:00 [received]
PHST- 2022/12/28 00:00 [accepted]
PHST- 2023/04/17 06:41 [medline]
PHST- 2023/03/15 06:00 [pubmed]
PHST- 2023/03/14 00:45 [entrez]
PHST- 2024/04/01 00:00 [pmc-release]
AID - 10.1038/s41588-023-01298-x [pii]
AID - 10.1038/s41588-023-01298-x [doi]
PST - ppublish
SO  - Nat Genet. 2023 Apr;55(4):595-606. doi: 10.1038/s41588-023-01298-x. Epub 2023 Mar 
      13.