The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors

Mark D Aupperlee; Anastasia Kariagina; Nicole Zaremba; Marc D Basson; Richard C Schwartz; Sandra Z Haslam

doi:10.1016/j.tranon.2018.02.011

The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors

Transl Oncol. 2018 Apr;11(2):518-527. doi: 10.1016/j.tranon.2018.02.011. Epub 2018 Mar 7.

Authors

Mark D Aupperlee¹, Anastasia Kariagina², Nicole Zaremba³, Marc D Basson⁴, Richard C Schwartz², Sandra Z Haslam⁵

Affiliations

¹ Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI; Department of Physiology, Michigan State University, East Lansing, MI. Electronic address: aupperl4@msu.edu.
² Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI.
³ Department of Surgery, University of Southern California, Los Angeles, CA.
⁴ Department of Surgery, University of North Dakota, Grand Forks, ND.
⁵ Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI; Department of Physiology, Michigan State University, East Lansing, MI.

Abstract

Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors.

Abstract

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