@article{4d85a921958a41acb793138c9d77ff4c,
title = "Loss of nuclear localized parathyroid hormone-related protein in primary breast cancer predicts poor clinical outcome and correlates with suppressed STAT5 signaling",
abstract = "Purpose: Parathyroid hormone-related protein (PTHrP) is required for normal mammary gland development and biology. A PTHLH gene polymorphism is associated with breast cancer risk, and PTHrP promotes growth of osteolytic breast cancer bone metastases. Accordingly, current dogma holds that PTHrP is upregulated in malignant primary breast tumors, but solid evidence for this assumption is missing. Experimental Design: We used quantitative IHC to measure PTHrP in normal and malignant breast epithelia, and correlated PTHrP levels in primary breast cancer with clinical outcome. Results: PTHrP levels were markedly downregulated in malignant compared with normal breast epithelia. Moreover, low levels of nuclear localized PTHrP in cancer cells correlated with unfavorable clinical outcome in a test and a validation cohort of breast cancer treated at different institutions totaling nearly 800 cases. PTHrP mRNA levels in tumors of a third cohort of 737 patients corroborated this association, also after multivariable adjustment for standard clinicopathologic parameters. Breast cancer PTHrP levels correlated strongly with transcription factors Stat5a/b, which are established markers of favorable prognosis and key mediators of prolactin signaling. Prolactin stimulated PTHrP transcript and protein in breast cancer cell lines in vitro and in vivo, effects mediated by Stat5 through the P2 gene promoter, producing transcript AT6 encoding the PTHrP 1-173 isoform. Low levels of AT6, but not two alternative transcripts, correlated with poor clinical outcome. Conclusions: This study overturns the prevailing view that PTHrP is upregulated in primary breast cancers and identifies a direct prolactin–Stat5–PTHrP axis that is progressively lost in more aggressive tumors.",
author = "Tran, {Thai H.} and Utama, {Fransiscus E.} and Takahiro Sato and Peck, {Amy R.} and Langenheim, {John F.} and Udhane, {Sameer S.} and Yunguang Sun and Chengbao Liu and Girondo, {Melanie A.} and Kovatich, {Albert J.} and Hooke, {Jeffrey A.} and Shriver, {Craig D.} and Hai Hu and Palazzo, {Juan P.} and Marluce Bibbo and Auer, {Paul W.} and Flister, {Michael J.} and Terry Hyslop and Mitchell, {Edith P.} and Inna Chervoneva and Hallgeir Rui",
note = "Funding Information: We thank Dr. David L. Rimm at the Department of Pathology, Yale University School of Medicine, New Haven, CT, for generously providing the cohort 2 tissue microarray and associated data for this study. The work was supported by Susan G. Komen for the Cure Promise grant KG091116, US National Institutes of Health grants CA188575 and CA185918, Worldwide Cancer Research grant WCR 14-0272, a grant from the Dr. Nancy Laning-Sobczak Fund for Breast Cancer awarded by the Medical College of Wisconsin Cancer Center, Institutional Research Grant #14-247-29 from the American Cancer Society and the MCW Cancer Center (to Y. Sun), and a postdoctoral fellowship grant P2BEP3_168705 from the Swiss National Science Foundation (to S.S. Udhane). The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army/Navy/Air Force, Department of Defense (DOD), or US Government. Funding Information: We thank Dr. David L. Rimm at the Department of Pathology, Yale University School of Medicine, New Haven, CT, for generously providing the cohort 2 tissue microarray and associated data for this study. The work was supported by Susan G. Komen for the Cure Promise grant KG091116, US National Institutes of Health grants CA188575 and CA185918, Worldwide Cancer Research grant WCR 14-0272, a grant from the Dr. Nancy Laning-Sobczak Fund for Breast Cancer awarded by the Medical College of Wisconsin Cancer Center, Funding Information: Institutional Research Grant #14-247-29 from the American Cancer Society and the MCW Cancer Center (to Y. Sun), and a postdoctoral fellowship grant P2BEP3_168705 from the Swiss National Science Foundation (to S.S. Udhane). The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army/Navy/Air Force, Department of Defense (DOD), or US Government. Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = dec,
day = "15",
doi = "10.1158/1078-0432.CCR-17-3280",
language = "English",
volume = "24",
pages = "6355--6366",
journal = "Clinical Cancer Research",
issn = "1078-0432",
number = "24",
}