Causes and Risk Factors for HER2-Positive Breast Cancer

HER2-positive breast cancer develops when breast cancer cells overproduce human epidermal growth factor receptor 2 (HER2), a protein that promotes cell growth and division. Although the reasons some breast cancers become HER2-positive are not fully understood, many of the same risk factors associated with breast cancer overall may play a role in its development.

According to the American Cancer Society, approximately 15% to 20% of breast cancers are HER2-positive. Historically, this subtype was associated with more aggressive tumor growth and a higher likelihood of recurrence. Today, advances in targeted therapies have significantly improved outcomes for many patients with HER2-positive breast cancer.

What causes HER2-positive breast cancer?

HER2-positive breast cancer occurs when breast cells acquire genetic changes that cause them to overproduce the HER2 protein. Normally, HER2 helps regulate cell growth and division, but when too much of the protein is present, cancer cells can grow and spread more rapidly.

Although the exact biological triggers are still being studied, several changes may contribute to the development of this subtype. These include:

• HER2 gene amplification and protein overexpression – Most HER2-positive breast cancers result from extra copies of the HER2 gene within cancer cells. This causes overproduction of the HER2 protein, which stimulates signals that promote uncontrolled cell growth and division.
• Acquired genetic mutations – Like other forms of breast cancer, HER2-positive breast cancer develops as genetic changes accumulate within breast cells over time. These mutations can disrupt normal cellular processes and contribute to cancer development.

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What are the risk factors for HER2-positive breast cancer? 

Researchers continue to explore potential reasons why certain breast cancers become HER2-positive. While many risk factors overlap with those for breast cancer overall, no specific lifestyle factor is definitively linked to HER2-positive disease alone.

Factors that may increase the risk of breast cancer, including HER2-positive disease, include:

• Older age – Although breast cancer can occur at any age, the risk increases over time.
• Female sex – Breast cancer occurs much more frequently in women than in men.
• Family history of breast cancer – Having one or more close relatives with breast cancer may increase the overall risk of developing breast cancer, including HER2-positive disease.
• Inherited genetic mutations – Certain inherited mutations, such as those in breast cancer gene 1 (BRCA1), breast cancer gene 2 (BRCA2) and partner and localizer of BRCA2 (PALB2), can increase the risk of developing breast cancer. However, HER2-positive breast cancer is typically driven by changes that occur within tumor cells rather than inherited alterations in the HER2 gene.
• Dense breast tissue – Women with dense breasts may have an increased risk of developing breast cancer, including HER2-positive tumors.
• Hormonal and reproductive factors – Factors that increase lifetime exposure to estrogen, such as early menstruation and late menopause, may increase breast cancer risk.
• Lifestyle-related factors – Alcohol consumption, excess body weight and physical inactivity are associated with an increased risk of breast cancer overall. Researchers continue to study whether these factors influence the development of HER2-positive disease.

Which risk factors for HER2-positive breast cancer are modifiable (factors you can control)?

Researchers have not identified any lifestyle factors that are known to specifically cause HER2-positive breast cancer. However, several health and lifestyle factors are associated with breast cancer overall and may influence the likelihood of developing HER2-positive disease.

Modifiable risk factors include:

• Alcohol consumption – Alcohol use is linked to an increased risk of breast cancer. Although researchers have not established a direct connection to HER2-positive tumors specifically, limiting alcohol intake may help reduce overall breast cancer risk.
• Weight management after menopause – Excess body weight following menopause is associated with an increased risk of breast cancer. Maintaining a healthy body weight may help lower that risk.
• Physical activity level – Regular exercise is associated with a lower risk of breast cancer and may help support healthy hormone levels, weight management and overall well-being.
• Use of menopausal hormone therapy – Long-term use of combined estrogen-progestin hormone therapy may increase breast cancer risk in some women. Patients should discuss the potential benefits and risks with their health care providers.
• Smoking and tobacco exposure – Some studies suggest that smoking may contribute to breast cancer development, particularly among individuals who smoke for many years. Avoiding tobacco products can support overall cancer prevention efforts.

Which risk factors for HER2-positive breast cancer are nonmodifiable (factors you cannot change)?

Some factors associated with HER2-positive breast cancer are biological or inherited and cannot be changed. Although these factors do not specifically cause HER2 overexpression, they may influence overall breast cancer risk and can provide important information for screening and risk assessment.

Nonmodifiable risk factors for HER2-positive breast cancer include:

• Female sex – HER2-positive breast cancer is diagnosed far more often in women than in men, largely because women typically have more breast tissue and greater lifetime exposure to breast-related hormonal changes.
• Older age – Although HER2-positive breast cancer can occur at any age, the overall likelihood of developing breast cancer increases over time.
• Family history of breast cancer – Having one or more close relatives with breast cancer may increase overall breast cancer risk. While family history does not specifically cause HER2-positive disease, it can help identify individuals who may benefit from enhanced screening or genetic counseling.
• Inherited cancer-related gene changes – Mutations in genes such as BRCA1, BRCA2 and PALB2 can increase the risk of developing breast cancer. However, HER2-positive tumors are usually linked to changes that occur within cancer cells rather than inherited changes in the HER2 gene.
• Breast density – Dense breast tissue may increase breast cancer risk and can make tumors more difficult to identify on mammograms. This can affect screening and follow-up recommendations for some patients.

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Can HER2-positive breast cancer be prevented?

Researchers have not identified any strategies that are proven to specifically prevent HER2-positive breast cancer. Nevertheless, maintaining good overall health, understanding personal risk factors and following recommended screening guidelines may help reduce overall breast cancer risk and improve the likelihood of early detection.

Strategies that may help support breast cancer prevention and early detection include:

• Discuss personal risk factors with a health care provider – HER2-positive breast cancer is defined by changes within tumor cells rather than a single known preventable cause. After reviewing an individual’s personal and family medical history, a health care provider can determine whether earlier screening, genetic counseling or additional monitoring may be appropriate.
• Follow breast cancer screening recommendations – Mammograms and other imaging tests cannot prevent HER2-positive breast cancer, but they may help detect breast cancer before symptoms develop. Earlier detection can allow treatment to begin sooner.
• Limit alcohol consumption – Alcohol use is associated with an increased risk of breast cancer overall. While reducing alcohol intake may help lower the risk, this strategy is not known to prevent HER2-positive breast cancer specifically.
• Stay physically active – Regular physical activity may help reduce overall breast cancer risk and support long-term health. Exercise can also play an important role in maintaining a healthy body weight.
• Maintain a body weight that supports overall health – Excess body weight, particularly after menopause, is linked to an increased risk of breast cancer. Weight management may help reduce overall risk, although it has not been shown to specifically prevent HER2-positive disease.
• Avoid tobacco use – Smoking is linked to many cancers and may contribute to breast cancer risk in some populations. Avoiding tobacco can support overall cancer prevention and general health.

Find the help you need for HER2-positive breast cancer at Moffitt Cancer Center

Because HER2-positive breast cancer behaves differently from other breast cancer subtypes, accurate tumor testing, diagnosis and specialized care are essential. The multispecialty team in Moffitt’s Don & Erika Wallace Comprehensive Breast Program has extensive experience evaluating HER2-positive tumors and developing individualized treatment plans that incorporate the latest advances in targeted therapy and other treatment options.

As a National Cancer Institute (NCI)-designated Comprehensive Cancer Center, Moffitt is committed to advancing the understanding and treatment of breast cancer through innovative research and patient-centered care.

If you would like to learn more about HER2-positive breast cancer, you can request an appointment with a specialist at Moffitt by calling 1-888-663-3488 or submitting a new patient registration form online. Referrals are not required.