STAT5 as a Molecular Target for Breast Cancer Prevention

Principal Investigator: LI, YI
Institution Receiving Award: BAYLOR COLLEGE OF MEDICINE
Program: BCRP
Proposal Number: BC112704
Award Number: W81XWH-12-1-0214
Funding Mechanism: Idea Expansion Award
Partnering Awards:
Award Amount: $586,093.00


Each year, approximately 200,000 new breast cancer cases are diagnosed in the United States. Thus, reducing breast cancer incidence even by a small percentage can have a profound impact on saving lives and reducing the huge costs associated with treatment. Antiestrogens (such as tamoxifen or raloxifene) are effective in reducing breast cancer risk in the high-risk population, but they still fail to prevent 40% of ER-positive cancers and have no impact on the incidence of ER-negative breast cancers. Furthermore, because any benefit is achieved only after years of treatment, women who do not yet have a clinically detectable breast lesion are often deterred from taking preventive antiestrogens. At present, breast cancer prevention efforts are stymied by little progress in discovering new drug prevention targets. To have a real prevention impact on women who have not yet developed clinical breast cancer, it is crucial to develop a prevention drug that has minimum side effects and does not require years of pills.

Designing more effective preventive strategies demands detailed knowledge of breast cancer formation. Breast early lesions such as ADH (atypical ductal carcinoma) are non-obligate precursors to invasive cancer, but what causes the progression of a small subset of these early lesions is not yet known. This knowledge could provide novel molecular targets for effective prevention of ER-positive and, more urgently, ER-negative breast cancers, and may unveil risk factors that could be valuable for predicting progression in at-risk women.

Using a novel mouse model that closely mimics human breast cancer initiation, we have discovered that apoptosis is especially important in suppressing progression from early lesions to breast cancer and that overcoming such an anticancer "barrier" is a critical step in the progression from early lesions to cancer. The overall goal of this proposal is, therefore, to identify the molecular mechanism by which the apoptosis anticancer barrier is overcome in progression from an early lesion to malignancy in the human breast.

Supported by our original Department of Defense Idea Award, we have found that the protein pSTAT5 plays a critical role in breaking the anti-apoptosis barrier, again using our unique mouse model. However, we do not know whether in women pSTAT5 is also responsible for progression from premalignant lesions to cancer. Therefore, in this application, we propose to test the hypothesis that in human breast cancer initiation, pSTAT5 promotes progression from ADH to cancer by lowering the apoptosis anticancer barrier, so that suppressing pSTAT5 could prevent breast cancer. We predict that even transient inhibition of this prosurvival pathway will devitalize early lesions and could lower the risk of breast cancer. With this short-term treatment approach, the possible adverse effects and the inconvenience to women would be small, so that they would not be discouraged from participating in this potentially highly effective cancer prevention strategy.

In testing our hypothesis, we have assembled a team including cancer biologists, a drug developer, and biostatisticians, and we will use a multi-pronged approach. We will use human breast cells both in culture and grown in mice; a novel human ADH model that my collaborator, Dr. Fariba Behbod at the University of Kansas Medical Center has developed; and our mouse model. Furthermore, we will make use of a novel inhibitor of pSTAT5 that has been invented by my co-investigator, Dr. David Tweardy. He has already shown that this inhibitor has no detectable toxicity in animal experiments and has high specificity for pSTAT5. We will examine whether this inhibitor can block progression from premalignant human breast cells to cancer cells in a mouse host.

If we are successful, pSTAT5 may be a molecular target for breast cancer prevention. Patients with pSTAT5-positive premalignant lesions may need to consider more aggressive prevention strategies including enrolment in clinical trials of pSTAT5 inhibitors. Clinical trials may also be warranted for high-risk patients including those who recently experienced a late-age first pregnancy, since we have found in the mouse that such a pregnancy can boost pSTAT5 levels in premalignant lesions. Again, we anticipate that this novel prevention strategy would have few adverse effects due to the need for only transient treatment using a tightly targeted drug.