ΔNp63 is regulated by insulin/IGF-1 signaling in normal
basal/progenitor mammary cells and in luminal-type breast
cancer cells

J 2023

ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells

ŠTENCKOVÁ, Michaela; Yajing LIU; Marta NEKULOVA; Jitka HOLCAKOVA; Zuzana POKORNA et al.

Základní údaje

Originální název

ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells

Autoři

ŠTENCKOVÁ, Michaela; Yajing LIU; Marta NEKULOVA; Jitka HOLCAKOVA; Zuzana POKORNA; Rudolf NENUTIL; Alastair M. THOMPSON; Borivoj VOJTESEK a Philip John COATES

Vydání

Neoplasma, AEPress, 2023, 0028-2685

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Slovensko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 2.000

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/23:00133617

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

breast cancer stem cells; ΔNp63; insulin; IGF-1; tumor microenvironment

Štítky

14314010, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 7. 3. 2024 11:18, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

Breast cancers are a heterogeneous group of tumors classified according to their histological growth patterns and receptor expression characteristics. Intratumor heterogeneity also exists, with subpopulations of cells with different phenotypes found in individual cancers, including cells with stem or progenitor cell properties. At least two types of breast cancer stem cells (CSCs) exist, the epithelial and the basal/mesenchymal subtypes, although how these phenotypes are controlled is unknown. ΔNp63 is a basal cell marker and regulator of stem/progenitor cell activities in the normal mammary gland and is expressed in the basal-like CSC subpopulation in some estrogen receptor-positive (ER+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast adenocarcinomas. Whilst p63 is known to directly impart CSC properties in luminal breast cancer cells, how p63 is regulated and induced in these cells is unknown. We initially confirmed the existence of a small subpopulation of ΔNp63+ cells in lymph node metastases of ER+ human ductal adenocarcinomas, indicating together with previous reports that ΔNp63+ tumor cells are present in approximately 40% of these metastases. Notably, ΔNp63+ cells show a preferential location at the edge of tumor areas, suggesting possible regulation of ΔNp63 by the tumor microenvironment. Subsequently, we showed that the high levels of ΔNp63 in basal non-transformed MCF-10A mammary epithelial cells rely on insulin in their culture medium, whilst ΔNp63 levels are increased in MCF-7 ER+ luminal-type breast cancer cells treated with insulin or insulin-like growth factor 1 (IGF-1). Mechanistically, small molecule inhibitors and siRNA gene knockdown demonstrated that induction of ΔNp63 by IGF-1 requires PI3K, ERK1/2, and p38 MAPK activation, and acts through FOXO transcriptional inactivation. We also show that metformin inhibits ΔNp63 induction. These data reveal an IGF-mediated mechanism to control basal-type breast CSCs, with therapeutic implications to modify intratumor breast cancer cell heterogeneity and plasticity.

Citovat

ŠTENCKOVÁ, Michaela; Yajing LIU; Marta NEKULOVA; Jitka HOLCAKOVA; Zuzana POKORNA; Rudolf NENUTIL; Alastair M. THOMPSON; Borivoj VOJTESEK a Philip John COATES. ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells. Neoplasma. AEPress, 2023, roč. 70, č. 5, s. 621-632. ISSN 0028-2685. Dostupné z: https://doi.org/10.4149/neo_2023_230719N376.

@article{2377102,
   author = {Štencková, Michaela and Liu, Yajing and Nekulova, Marta and Holcakova, Jitka and Pokorna, Zuzana and Nenutil, Rudolf and Thompson, Alastair M. and Vojtesek, Borivoj and Coates, Philip John},
   article_number = {5},
   doi = {https://doi.org/10.4149/neo_2023_230719N376},
   keywords = {breast cancer stem cells; ΔNp63; insulin; IGF-1; tumor microenvironment},
   language = {eng},
   issn = {0028-2685},
   journal = {Neoplasma},
   title = {ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells},
   url = {http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=8205&category_id=189&option=com_virtuemart&vmcchk=1&Itemid=1},
   volume = {70},
   year = {2023}
}

TY  - JOUR
ID  - 2377102
AU  - Štencková, Michaela - Liu, Yajing - Nekulova, Marta - Holcakova, Jitka - Pokorna, Zuzana - Nenutil, Rudolf - Thompson, Alastair M. - Vojtesek, Borivoj - Coates, Philip John
PY  - 2023
TI  - ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells
JF  - Neoplasma
VL  - 70
IS  - 5
SP  - 621-632
EP  - 621-632
PB  - AEPress
SN  - 00282685
KW  - breast cancer stem cells
KW  - ΔNp63
KW  - insulin
KW  - IGF-1
KW  - tumor microenvironment
UR  - http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=8205&category_id=189&option=com_virtuemart&vmcchk=1&Itemid=1
N2  - Breast cancers are a heterogeneous group of tumors classified according to their histological growth patterns and receptor expression characteristics. Intratumor heterogeneity also exists, with subpopulations of cells with different phenotypes found in individual cancers, including cells with stem or progenitor cell properties. At least two types of breast cancer stem cells (CSCs) exist, the epithelial and the basal/mesenchymal subtypes, although how these phenotypes are controlled is unknown. ΔNp63 is a basal cell marker and regulator of stem/progenitor cell activities in the normal mammary gland and is expressed in the basal-like CSC subpopulation in some estrogen receptor-positive (ER+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast adenocarcinomas. Whilst p63 is known to directly impart CSC properties in luminal breast cancer cells, how p63 is regulated and induced in these cells is unknown. We initially confirmed the existence of a small subpopulation of ΔNp63+ cells in lymph node metastases of ER+ human ductal adenocarcinomas, indicating together with previous reports that ΔNp63+ tumor cells are present in approximately 40% of these metastases. Notably, ΔNp63+ cells show a preferential location at the edge of tumor areas, suggesting possible regulation of ΔNp63 by the tumor microenvironment. Subsequently, we showed that the high levels of ΔNp63 in basal non-transformed MCF-10A mammary epithelial cells rely on insulin in their culture medium, whilst ΔNp63 levels are increased in MCF-7 ER+ luminal-type breast cancer cells treated with insulin or insulin-like growth factor 1 (IGF-1). Mechanistically, small molecule inhibitors and siRNA gene knockdown demonstrated that induction of ΔNp63 by IGF-1 requires PI3K, ERK1/2, and p38 MAPK activation, and acts through FOXO transcriptional inactivation. We also show that metformin inhibits ΔNp63 induction. These data reveal an IGF-mediated mechanism to control basal-type breast CSCs, with therapeutic implications to modify intratumor breast cancer cell heterogeneity and plasticity.
ER  -

ŠTENCKOVÁ, Michaela; Yajing LIU; Marta NEKULOVA; Jitka HOLCAKOVA; Zuzana POKORNA; Rudolf NENUTIL; Alastair M. THOMPSON; Borivoj VOJTESEK a Philip John COATES. ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells. \textit{Neoplasma}. AEPress, 2023, roč.~70, č.~5, s.~621-632. ISSN~0028-2685. Dostupné z: https://doi.org/10.4149/neo\_{}2023\_{}230719N376.

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