Triple-Negative Breast Cancer Causes and Risk Factors

Triple-negative breast cancer (TNBC) develops when breast cells acquire genetic changes that allow them to grow and divide uncontrollably, eventually forming a tumor. This biologically distinct subtype is classified as “triple-negative” because TNBC cells do not have estrogen receptors (ER) or progesterone receptors (PR) and do not overexpress the human epidermal growth factor receptor 2 (HER2) protein. 

Although the exact cause of TNBC remains unknown, researchers have identified several factors that may increase the risk, including inherited BRCA1 gene mutations, younger age and a personal or family history of breast or ovarian cancer.

Triple-negative breast cancer accounts for approximately 10% to 15% of all breast cancer diagnoses. Compared with many other breast cancer subtypes, TNBC is more likely to grow and spread quickly. However, advances in chemotherapy, immunotherapy and targeted therapy for appropriate patients continue to improve outcomes. 

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What causes triple-negative breast cancer? 

Researchers do not yet fully understand why some breast cancers develop as triple-negative while others express hormone receptors or HER2. However, several biological mechanisms are associated with TNBC development. These include:

• Acquired DNA changes – Most TNBC cases develop after genetic mutations arise within breast cells during a person’s lifetime. These changes can disrupt the normal mechanisms that regulate cell growth and division.
• Alterations in DNA repair genes – Mutations affecting genes responsible for repairing damaged DNA may allow abnormal breast cells to survive and multiply.
• Inherited genetic mutations – Some individuals inherit gene mutations that increase susceptibility to breast cancer. BRCA1 mutations are particularly associated with triple-negative breast cancer.
• Abnormal cellular signaling – Researchers continue to investigate molecular pathways that influence the growth, survival and spread of triple-negative breast cancer cells.

What are the risk factors for triple-negative breast cancer?  

Although anyone can develop TNBC, certain characteristics are more strongly associated with this subtype than with other forms of breast cancer. Risk factors for triple-negative breast cancer include:

• Inherited BRCA1 gene mutations – Individuals with BRCA1 mutations have a significantly higher likelihood of developing TNBC than the general population.
• Other inherited gene mutations – Alterations in genes such as BRCA2, PALB2 and TP53 may increase breast cancer risk.
• Younger age – Compared with other breast cancer subtypes, triple-negative breast cancer is diagnosed more often in women younger than 50.
• Black race – Studies show that Black women have a higher incidence of TNBC than women of most other racial and ethnic groups. The reasons for this difference are not fully understood and continue to be studied.
• Female sex – Like other forms of breast cancer, TNBC occurs much more frequently in women than in men.
• Family history of breast or ovarian cancer – A strong family history may suggest an inherited cancer predisposition syndrome that increases the risk of triple-negative breast cancer.

Which risk factors for triple-negative breast cancer are nonmodifiable?

Several risk factors associated with TNBC cannot be changed. Recognizing these characteristics may help individuals better understand their risk and determine whether genetic counseling or additional risk assessment may be appropriate. Nonmodifiable risk factors for triple-negative breast cancer include:

• Inherited BRCA1 gene mutations – BRCA1 mutations are among the strongest known inherited risk factors for TNBC.
• Younger age – Compared with many other breast cancer subtypes, TNBC is diagnosed more frequently in women younger than 50.
• Black race – Black women are more likely than women of other racial and ethnic groups to develop TNBC.
• Female sex – Women account for the vast majority of triple-negative breast cancer diagnoses.
• Family history – A family history of breast or ovarian cancer may suggest an inherited genetic predisposition that increases the risk of TNBC.

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Which risk factors for triple-negative breast cancer are modifiable?

Researchers have not identified any lifestyle factors that are known to specifically cause TNBC. However, several modifiable factors are associated with breast cancer overall, and researchers continue to study how they may influence the risk of developing the triple-negative subtype. Potentially modifiable risk factors include:

• Alcohol consumption – Drinking is associated with an elevated risk of breast cancer overall, although its relationship to TNBC is less clearly defined.
• Excess body weight – Being overweight or obese, particularly after menopause, is linked to an increased risk of developing breast cancer. Researchers continue to study how excess body weight may influence the risk of TNBC.
• Physical inactivity – Regular physical activity is associated with a lower risk of breast cancer overall. Although its effect on TNBC remains under investigation, maintaining an active lifestyle supports overall health.
• Smoking – Some studies suggest that tobacco use may increase the likelihood of developing triple-negative breast cancer, although the evidence is not as consistent as it is for other cancer types.
• Long-term use of combined menopausal hormone therapy – Combined estrogen-progestin hormone therapy is associated with an increased risk of breast cancer overall, although its relationship to TNBC is not well established.
• Breastfeeding history – Some studies suggest that breastfeeding may reduce the risk of developing TNBC, particularly among women with BRCA1 mutations and those otherwise at heightened risk. Researchers continue to investigate this association.

Can triple-negative breast cancer be prevented?

Because the exact cause of TNBC remains unclear, there is no proven way to prevent this specific breast cancer subtype. However, the following measures may help identify inherited risk, support earlier detection and promote overall breast health:

• Discussing family medical history – Sharing information about breast, ovarian and other hereditary cancers with family members and a healthcare provider can help guide recommendations for genetic testing and screening.
• Considering genetic counseling – Individuals with a strong family history of breast or ovarian cancer may benefit from genetic counseling to better understand their inherited cancer risk.
• Following recommended breast cancer screening guidelines – Mammograms, breast magnetic resonance imaging (MRI) for individuals at elevated risk and other screening tests can help detect breast cancer before symptoms develop.
• Maintaining a healthy lifestyle – Eating a balanced diet, staying physically active and limiting alcohol consumption may help reduce the risk of breast cancer.
• Reporting breast changes promptly – Any new breast lump, skin change, nipple discharge or other concerning symptom should be evaluated by a physician.

Find the help you need for triple-negative breast cancer at Moffitt Cancer Center

Understanding the causes and risk factors associated with TNBC can help guide decisions about screening, genetic testing and treatment. At Moffitt, the multispecialty team in the Don & Erika Wallace Comprehensive Breast Program provides comprehensive risk assessments, advanced diagnostic testing and personalized treatment plans for patients with triple-negative breast cancer and other breast cancer subtypes.

If you would like to learn more about triple-negative breast cancer causes, risk factors or treatment options, you can request an appointment with a specialist at Moffitt by calling 1-888-663-3488 or submitting a new patient registration form online. We do not require referrals.