Ambrosone Christine B, Yao Song, Long Mark D, Liu Chunyu, Chen Jianhong, Davis Warren, Zirpoli Gary, Payne-Ondracek Rochelle, Khoury Thaer, Gong Zhihong, Hu Qiang, Szewczyk Sirinapa, Omilian Angela R, Bandera Elisa V, Liu Song, Kushi Lawrence, Higgins Michael J, Palmer Julie R
Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA.
BMJ Oncol. 2025 Mar 3;4(1):e000675. doi: 10.1136/bmjonc-2024-000675. eCollection 2025.
Having children reduces risk of breast cancer overall, but parity without breastfeeding, more prevalent among black women, increases risk of poor-prognosis oestrogen receptor negative (ER-) breast cancer. We investigated if relationships between parity, breastfeeding and ER subtypes result from epigenetic programming, potentially steering breast progenitor cells to a basal-like phenotype.
The Illumina MethylationEPIC platform was used to assess genome-wide methylation in formalin-fixed, paraffin-embedded tumours from 1459 Black women with breast cancer. Methylation was evaluated in relation to parity, breastfeeding and breast cancer subtypes in a case-only analysis, with methylation-gene expression pairs tested in a subset of cases. We then performed functional enrichment analysis for probes significantly associated with parity and breastfeeding.
Among women who did not breastfeed (n=634), there were 500 significant (p<1e-5) differentially methylated loci (DML) by parity, compared with only five DMLs among women who had breastfed their children (n=568). One of the top DML genes was , pivotal in governing the luminal lineage of progenitor cells, with a statistically significant interaction (p=0.04) for number of births and breastfeeding. Associations were strongest for ER- disease.
In this large study of Black women with breast cancer, we elucidated biological pathways for the observed associations between parity without breastfeeding and breast cancer subtypes, revealing distinct molecular alterations in breast DNA, particularly for ER- tumours. Black women in the USA tend to have more children and are less likely to breastfeed; their breast cancer risk may be reduced by societal systems that promote and support breastfeeding.
生育子女总体上可降低患乳腺癌的风险，但未进行母乳喂养的生育情况在黑人女性中更为普遍，这会增加预后不良的雌激素受体阴性（ER-）乳腺癌的风险。我们调查了生育情况、母乳喂养与ER亚型之间的关系是否源于表观遗传编程，这种编程可能会将乳腺祖细胞导向基底样表型。
使用Illumina MethylationEPIC平台评估1459名患有乳腺癌的黑人女性的福尔马林固定石蜡包埋肿瘤中的全基因组甲基化情况。在仅病例分析中评估甲基化与生育情况、母乳喂养及乳腺癌亚型的关系，并在部分病例中测试甲基化-基因表达对。然后对与生育情况和母乳喂养显著相关的探针进行功能富集分析。
在未进行母乳喂养的女性（n = 634）中，根据生育情况有500个显著（p < 1e - 5）的差异甲基化位点（DML），而在进行母乳喂养的女性（n = 568）中只有5个DML。其中一个顶级DML基因是 ，它在调控祖细胞的管腔谱系中起关键作用，生育次数与母乳喂养之间存在统计学显著的相互作用（p = 0.04）。ER-疾病的关联最为强烈。
在这项针对患有乳腺癌的黑人女性的大型研究中，我们阐明了未进行母乳喂养的生育情况与乳腺癌亚型之间观察到的关联的生物学途径，并揭示了乳腺DNA中不同的分子改变，特别是对于ER-肿瘤。美国的黑人女性往往生育更多子女且母乳喂养的可能性较小；促进和支持母乳喂养的社会体系可能会降低她们患乳腺癌的风险。
