Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.

Autor:	Diep CH; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., Spartz A; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., Truong TH; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., Dwyer AR; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA., El-Ashry D; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA., Lange CA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.; Department of Medicine, Division of Hematology, Oncology & Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2024 Jul 26; Vol. 165 (9).
DOI:	10.1210/endocr/bqae092
Abstrakt:	Breast cancer progression involves intricate interactions between cancer cells and the tumor microenvironment (TME). This study elucidates the critical role of progesterone receptor (PR) signaling in mediating the protumorigenic effects of cancer-associated fibroblasts (CAFs) on estrogen receptor-positive (ER+) luminal breast cancer cells. We demonstrate that CAFs produce physiologically relevant levels of estrogen and progesterone, which significantly contribute to breast cancer tumorigenicity. Specifically, CAF conditioned media (CM) promoted PR-dependent anchorage-independent growth, tumorsphere formation/stem cell expansion, and CD44 upregulation. CAF cells formed co-clusters more frequently with PR+ breast cancer cells relative to PR-null models. While both PR isoforms mediated these actions, PR-A was a dominant driver of tumorsphere formation/stemness, while PR-B induced robust CD44 expression and CAF/tumor cell co-cluster formation. CD44 knockdown impaired CAF/tumor cell co-clustering. Fibroblast growth factor 2 (FGF2), also secreted by CAFs, phosphorylated PR (Ser294) in a MAPK-dependent manner and activated PR to enhance CD44 expression and breast cancer tumorigenicity. The FGF receptor (FGFR) inhibitor PD173074 diminished CAF- and FGF2-dependent PR activation, tumorsphere formation, and co-clustering. In summary, this study reveals a novel mechanism through which stromal CAFs orchestrate elevated PR signaling in ER+ luminal breast cancer via secretion of both progesterone and FGF2, a potent activator of ERK1/2. Understanding tumor cell/TME interactions provides insights into potential therapeutic strategies aimed at disrupting PR- and/or FGF2/FGFR-dependent signaling pathways to prevent early metastasis in patients with ER+ breast cancer. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)
Databáze:	MEDLINE
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