Association of reproductive history with breast tissue characteristics and receptor status in the normal breast

Marike Gabrielson, Flaminia Chiesa, Catharina Behmer, Katarina Rönnow, Kamila Czene, Per Hall, Marike Gabrielson, Flaminia Chiesa, Catharina Behmer, Katarina Rönnow, Kamila Czene, Per Hall

Abstract

Introduction: Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma).

Materials and methods: Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI.

Results: Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial-stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among postmenopausal women. Prior use of oral contraceptives was associated with lower epithelial-stromal ratio amongst all participants and among pre- and postmenopausal women separately.

Conclusion: Reproductive risk factors significantly influence the epithelial tissue compartment and expression of hormone receptors in later life. These changes remain after menopause. This study provides deeper insights of the biological mechanisms by which reproductive history influences epithelial area and expression of hormone receptors, and as a consequence the risk of breast cancer.

Keywords: Breast tissue histology; Epithelial breast tissue; Hormone receptor status; Proliferation; Reproductive history; Reproductive score.

Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The study was approved by the ethical review board at Karolinska Institutet. Informed consent was obtained from all individual participants included in the study. All experiments comply with the current Swedish laws.

Figures

Fig. 1
Fig. 1
Multivariable regression plots of percentage epithelial tissue (log) by reproductive risk factors and reproductive score in postmenopausal women. The reproductive score was generated by summarising the number of reproductive events defined by parity (no = 0, yes = 1), number of pregnancies without births, number of births, age at first birth (nulliparous = 0,  25 = 3), and minimum duration of breastfeeding (0,  group mean = 2). All analyses are adjusted for age and BMI. X-axes represent arbitrary numbers of the individual reproductive factors from normalised log-transformed linear regression models
Fig. 2
Fig. 2
Multivariable regression plots of percentage epithelial oestrogen receptor (ER) expression (log) by reproductive risk factors and reproductive score in postmenopausal women. The reproductive score was generated by summarising the number of reproductive events defined by parity (no = 0, yes = 1), number of pregnancies without births, number of births, age at first birth (nulliparous = 0,  25 = 3), and minimum duration of breastfeeding (0,  group mean = 2). All analyses are adjusted for age and BMI. X-axes represent arbitrary numbers of the individual reproductive factors from normalised log-transformed linear regression models

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