June 4, 2021/Cancer/Genomics

Inherited Risk of Estrogen-Driven Postmenopausal Breast Cancer

Adrenal-permissive HSD3B1 plays a role

16-HRT-144-GeneticsCardiomyopathies-CQD-650×450 (2)

Homozygous inheritance of a common missense-encoding germline variation in HSD3B1 is associated with estrogen-driven postmenopausal breast cancer, according to a Cleveland Clinic study recently presented at the American Society of Clinical Oncology 2021 annual meeting.


Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

“Previous research has shown that the 1245C variation in HSD3B1 confers high enzyme stabilization, creating an adrenal permissive allele that varies in frequency among different populations, but is fairly common in white populations,” says Nima Sharifi, MD, Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic Cancer Center and senior author of the abstract. “We wanted to determine whether this genotype makes a difference in sex steroid-associated outcomes for patients who don’t have gonadal sex steroids, in postmenopausal women with estrogen-driven breast cancer, where HSD3B1 is necessary for estrogen production. We already know it is important in men with prostate cancer treated with medical castration because of its role in androgen production.”

Prospective and validation cohorts

Researchers conducted a prospective, single-institution study to determine the presence and frequency of the homozygous adrenal-permissive HSD3B1 genotype and circulating steroid concentrations compared with the frequency of the homozygous adrenal permissive HSD3B1 genotype in general and in patients with stages I-III estrogen-dependent breast cancer. The team also conducted a validation study using the Cambridge and The Cancer Genome Atlas genomic datasets, which have estrogen receptor documentation. Frequency of the adrenal-permissive genotype in both patients with postmenopausal estrogen receptor-positive breast cancer and in the general population was the primary outcome measured. Researchers also compared genotypes with postmenopausal estrogen receptor-negative breast cancer patients and determined any genotype associations with circulating adrenal androgen concentrations.

The prospective study enrolled 199 women, with 187 included in the final analysis, while the validation studies included 1628 women. The frequency of the adrenal-permissive genotype in white, postmenopausal women with estrogen-driven breast cancer was 17.5% in the prospective cohort, compared with only 9.6% in the general population (P = 0.0077). When validated with the independent genomic datasets, the frequency of the adrenal-permissive genotype was 14.4% compared with 6% for patients with estrogen receptor-negative breast cancer (P = 0.007) and the general population (P = 0.005).


The researchers also determined circulating androstenedione was at a significantly higher concentration in women with the adrenal-permissive genotype compared with other genotypes (P = 0.03).

Linking germline inheritance to breast cancer

“To our knowledge, this is the first-known mechanism that links germline inheritance to endogenous estrogen exposure and breast cancer,” says Dr. Sharifi. “We think that HSD3B1 genetics may account for about five percent of estrogen-driven postmenopausal breast cancers, and that this may be a factor in population differences in predisposition and outcomes.”

Linking genetic inheritance of endogenous estrogen exposure to postmenopausal estrogen-driven breast cancer is a significant advancement in the understanding of estrogen physiology as it relates to breast cancer in postmenopausal women. “Our findings have broad potential implications for clinical practice, in the realms of prevention and risk stratification, and potentially biomarkers to predict hormonal therapy response,” says Dr. Sharifi. Megan Kruse, MD, hematologist/oncologist at Cleveland Clinic Cancer who specializes in breast cancer, collaborated with Dr. Sharifi on this research.


Next steps for the research team include pinpointing the implications of HSD3B1 genetics on clinical outcomes with hormonal therapy in breast cancer as well as conducting additional validation studies with other patient cohorts.

Related Articles

23-CNR-3647478-CQD-Hero-650×450 Dr Scott Dr Scarborough
April 27, 2023/Cancer/Genomics
Gene Expression Signature Predicts Patients’ Response to Cisplatin

Research enables precision medicine beyond patients with changed mutational status

Cancer cell, cell grow out of control and become invasive
July 12, 2022/Cancer/Genomics
Evolutionary Games Have High Stakes in Treatment-Resistant Cancer

Understanding cell growth dynamics may be key to controlling therapeutic resistance

Doctor Talking With a Cancer Patient During Treatment
December 21, 2021/Cancer/Genomics
Survivorship is the Focus of New Cancer Genomics Program

Specialized clinic addresses long-term wellness through the study of somatic mutations

June 24, 2021/Cancer/Genomics
Breastfeeding Cuts Ovarian Cancer Risk in BRCA Mutation Carriers

Other reproductive and hormonal factors found protective

June 7, 2021/Cancer/Genomics
New Polygenic Risk Score for Breast Cancer Accurate for All Ancestries

Improved risk stratification for all women

PTEN flip-Lerner
March 26, 2021/Cancer/Genomics
Cleveland Clinic Designated PTEN Clinical Center of Excellence

Clinicians and researchers with unique expertise