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Clinical association of progesterone receptor isoform A with breast cancer metastasis consistent with its unique mechanistic role in preclinical models.

Abstract：

BACKGROUND:Luminal breast cancer (L-BCa) comprises the majority of incurable, distally metastatic breast cancer cases. Estrogen supports growth of L-BCa cells but suppresses invasiveness. Estrogen also induces the progesterone receptor (PR). Invasiveness and metastasis of L-BCa cells is supported by the short PR isoform (PR-A), in response to the range of pre- and post-menopausal plasma hormone levels, by counteracting the effects of estrogen via micro RNA-mediated cross-talk with the estrogen receptor (ER). PR-B directly supports L-BCa invasion and metastasis and also inhibits tumor growth, both only at high progesterone levels. As public datasets on L-BCa tumors cannot distinguish PR-A, this study was designed to seek clinical evidence for the role of PR-A in metastasis in comparison with PR-B and ER. METHODS:Measurement of tumor PR-A, PR-B and ER mRNA expression in 125 treatment-naive primary L-BCa patients with differential node involvement and analysis using linear mixed effects models. Transcriptional activity assays of PR-A and PR-B. RESULTS:Lymph node involvement was strongly associated with PR-A expression (median, 3-fold higher vs. node-negative), independent of age, pathologic type, tumor grade, HER2 and PR-B. PR-B and ER correlated weakly with PR-A, but whereas PR-B and the PR-A/PR-B ratio were not significantly associated with node involvement, ER weakly negatively correlated with node positivity. PR-A was hypersensitive to mifepristone compared with PR-B. CONCLUSIONS:Taken together with previous mechanistic studies, the findings provide clinical evidence in support of the role of PR-A in L-BCa metastasis. They also suggest the possibility of developing selective PR-A modulators for future interventions in appropriate clinical situations.

journal_name

BMC Cancer

journal_title

BMC cancer

authors

Rosati R,Oppat K,Huang Y,Kim S,Ratnam M

doi

10.1186/s12885-020-07002-0

subject

Has Abstract

pub_date

2020-06-03 00:00:00

pages

512

issue

issn

1471-2407

pii

10.1186/s12885-020-07002-0

journal_volume

pub_type

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Clinical association of progesterone receptor isoform A with breast cancer metastasis consistent with its unique mechanistic role in preclinical models.