Abstract: Triple-negafive (TN) (tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER2) and HER2-overexpressing (H2E) (tumors that are ER-/HER2+) breast cancers are two particularly aggressive molecular subtypes of breast cancer that disproportionately impact Hispanic women and other medically disadvantaged populations. However, factors influencing their etiologies and prognoses are largely unknown, and none of the few studies assessing these questions have included a meaningful number of Hispanic cases. To address this existing research gap, we propose a population-based case-case study of breast cancer among women aged 20-69 years in the Seattle, Washington and Albuquerque, New Mexico greater metropolitan areas. This study will include 1120 TN, 600 H2E, and 1120 luminal (ER+) invasive breast cancer cases, including 175 TN, 90 H2E, and 175 luminal cases that are Hispanic. Detailed medical record reviews will be conducted to ascertain data on numerous breast cancer risk factors. With a sample size that is substantially larger than any other published study of these tumor types, a focus on the age range over which these tumors are most common, and inclusion of a substanfial number of Hispanic cases, this study will enable us to address the following new quesfions: 1. How are established breast cancer risk factors, including reproductive factors, anthropometric measures, mammographic density, and family history of breast cancer, related to risks of TN and H2E breast cancer relative to risk of luminal breast cancer? Several studies with limited sample sizes indicate that TN, H2E and luminal breast cancers have different risk factor proflles, but these results require confirmation in a larger population-based setfing. Given that most breast cancer risk factors confer elevated risks of breast cancer independent of race/ethnicity, identifying TN and H2E specific risk factors could have broad public health importance and provide important insight Into the contributors to the higher incidence rates of these two aggressive types of breast cancer that both Hispanics and African Americans experience. 2. Do the associations between established risk factors and risks of TN and H2E breast cancer differ among Hispanics and non-Hispanics? While most risk factors are unlikely to difl'er in their associafion with TN and H2E by Hispanic ethinicity, there is some data to suggest that some, like family history, might A strength of our study is the incorporation of genetic ancestry when defining women as Hispanic. 3. How do established breast cancer risk factors influence risk of mortality among women diagnosed with TN and H2E breast cancers? Several epidemiologic risk factors, notably obesity, influence risk of mortality among breast cancer survivors. However, no prior studies have assessed how such risk factors may differentially impact risk of mortality among TN and H2E breast cancer survivors.