Postmenopausal Duration, Local Estrogen Biosynthesis, and Receptor-Driven Tumorigenesis: A Multiregional Molecular Epidemiological Study of Breast and Uterine Cancers in Indonesia
Agussalim*, Citrawati, Muhammad Saleng, Muhammad Basri, Hj Rahmatiah, Ruqaiyah and Fauziah Botutihe
ABSTRACT
Background: Postmenopausal status is known to influence the risk of hormonally‐driven malignancies such as breast and uterine cancers, via changes in estrogen/progesterone levels, receptor expression, and related molecular pathways. However, data from specific Indonesian regions remain scarce.
Objectives: To investigate the correlation between postmenopausal status and incidence of breast and uterine cancer in six regions of Eastern/Southern Sulawesi and Central Sulawesi (Manado, Gorontalo, Palu, Mamuju, Makassar, Kendari) during January–December 2024, with a focus on biomolecular markers such as estrogen receptor (ER), progesterone receptor (PR), HER2, and local estrogen synthesis (e.g. aromatase expression).
Methods: This correlational epidemiological study collected clinical and pathological data on 115 postmenopausal women diagnosed with either breast cancer or uterine (endometrial) cancer between 1 January and 31 December 2024, from major hospitals in Manado, Gorontalo, Palu, Mamuju, Makassar, and Kendari. Inclusion criteria: women ≥45 years, confirmed postmenopausal (no menses for ≥12 months), histologically confirmed breast or uterine cancer. Biomolecular assays included immunohistochemistry (IHC) for ER, PR, HER2; RT‐PCR quantification of aromatase (CYP19A1) and 17β‐hydroxysteroid dehydrogenase isoforms in tumour tissue; measurement of circulating estrone / estradiol levels; and assessment of nuclear proliferation marker Ki‐67. Ethical clearance was granted by Palu, No. EC/980/I/2024. Statistical Analyses: Chi‐square tests for categorical variables, t‐tests or Mann‐Whitney U for continuous markers, logistic regression to assess odds ratios (OR) of receptor positivity or high proliferation associated with postmenopausal duration, adjusting for age, BMI, region. Significance threshold p < 0.05.
Results: Of 115 cases, 75 had breast cancer, 40 had uterine cancer. Mean age was 61.2 ± 6.8 years. Duration since menopause averaged 12.3 ± 5.1 years. ER positivity among breast cancer cases was 82.7%, PR positivity 68.0%, HER2 overexpression in 22.7%. Uterine cancers showed overexpression of ER in 70.0%, PR in 60.0%. Aromatase and 17β‐HSD type 1 expression in tumor tissue were significantly elevated in both cancer types (mean fold‐change vs adjacent non-cancer tissue: breast 3.5 and 2.8; uterine 3.1 and 2.5 respectively; p < 0.01). High Ki‐67 (>20%) was observed in 60% of breast cancers and 55% of uterine cancers. Logistic regression showed that longer postmenopausal duration (>10 years) was strongly associated with ER positivity in breast cancer (OR 2.8; 95% CI 1.4-5.6; p = 0.003) and uterine cancer (OR 2.3; 95% CI 1.1-4.9; p = 0.02). Similar associations for aromatase overexpression and elevated estrone levels. The correlation coefficients among biomarkers (ER, PR, aromatase, Ki‐67) were high (r = 0.65 ‒ 0.78), all p < 0.001.
Conclusions: In this cohort from multiple Indonesian regions, postmenopausal status, especially longer duration since menopause, is significantly correlated with increased incidence and molecular biomarker expression of breast and uterine cancer. Elevated estrogenic activity in tumor tissue (via aromatase, 17β-HSD) and high proliferation (Ki-67) likely underlie these associations. These findings suggest potential benefits of screening and preventive strategiestargeting receptor status and local estrogen synthesis in postmenopausal women.
