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Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

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Abstract

Estrogen receptor (ER) is essential for estrogen-dependent growth, and its level of expression is considered a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer. On the other hand, the clinical role of progesterone receptor (PgR) in ER-positive breast cancer remains controversial, although testing of PgR by immunohistochemistry (IHC) has become routine. Recent studies indicated that plasma estradiol levels were related to the expression levels of estrogen-responsive genes in ER-positive breast cancer tissues in both pre- and postmenopausal women. In this study, we analyzed the expression levels of estrogen-responsive genes (PgR and TFF1), a progesterone-responsive gene (RANKL), ER-related genes (FOXA1 and GATA3), HER2, Ki67 and p53 in ER-positive, HER2-negative breast cancer tissues by IHC. Correlations between the expression levels of these molecular markers and clinicopathological factors, including prognosis, were compared between pre- and postmenopausal women. Serum levels of estrone, estradiol, progesterone, and testosterone were also measured. Expression levels of PgR, TFF1, RANKL, and GATA3 were significantly higher in premenopausal women than in postmenopausal women. Serum estradiol levels were positively correlated with Ki67 labeling index (LI) in premenopausal women, but not in postmenopausal women. High expression of FOXA1 and GATA3 was significantly associated with improved disease-free survival in premenopausal women, but not in postmenopausal women, whereas high expression of PgR and low expression of p53 were significantly correlated with the improved disease-free survival in postmenopausal women, but not in premenopausal women. Moreover, the best cutoff points of Ki67 LI for disease-free survival were 30 % for premenopausal women and 14 % for postmenopausal women. Expression levels of ER, TFF1, and RANKL were not associated with the disease-free survival in either pre- or postmenopausal women. Our results suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status.

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Abbreviations

ER:

Estrogen receptor

PgR:

Progesterone receptor

TFF1:

Trefoil factor 1

RANKL:

Receptor activator of NF-kappa B ligand

FOXA1:

Forkhead box A1

GATA3:

GATA binding protein 3

HER2:

Human epidermal growth factor receptor type 2

Ki67 LI:

Ki67 labeling index

IHC:

Immunohistochemistry

BMI:

Body mass index

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Acknowledgments

The authors thank Mr. Jun Moriya and Mrs. Mikiko Sato for their technical assistance.

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Authors and Affiliations

  1. Breast and Endocrine Surgery, Hokkaido University Hospital, Kita 14 Nishi 5, Kita-ku, Sapporo, 060-8648, Japan

    Mitsuchika Hosoda, Mitsugu Yamamoto, Kiichiroh Nakano & Hiroko Yamashita

  2. Department of Surgical Pathology, Hokkaido University Hospital, Kita 14 Nishi 5, Kita-ku, Sapporo, 060-8648, Japan

    Kanako C. Hatanaka, Emi Takakuwa, Yutaka Hatanaka & Yoshihiro Matsuno

  3. Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita 14 Nishi 5, Kita-ku, Sapporo, 060-8648, Japan

    Emi Takakuwa, Yutaka Hatanaka & Yoshihiro Matsuno

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  1. Mitsuchika Hosoda
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Correspondence to Hiroko Yamashita.

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Hosoda, M., Yamamoto, M., Nakano, K. et al. Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 144, 249–261 (2014). https://doi.org/10.1007/s10549-014-2867-0

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  • DOI: https://doi.org/10.1007/s10549-014-2867-0

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